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ABO Incompatible Stem Cell Transplantation






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ABO Incompatible Stem Cell Transplantation

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1. ABO Incompatible Stem Cell Transplantation Armin Ghobadi, MD Fellow, Hematology & Oncology Washington University in St Louis 3/4/2011 1

2. Disclosure I have NO financial relationships to disclose 2

3. Overview Case ABO blood group Minor ABO mismatch Major ABO mismatch Survival and ABO incompatibility GvHD and ABO incompatibility 3

4. Case 26 y/o M with relapsed refractory cutaneous PTCL FTBI/Cy HLA identical sib-allo on 2/8/10 ABO: Patient: O+ Donor: B+ Neutrophil engraftment: 16 days PLT engraftment: 24 days 4

5. Case 5

6. ABO-Rh Blood group 6

7. Classification ABO-incompatible HSCT: 30%-40% 7

8. ABO mismatch potential complications Minor ABO mismatch: Passenger lymphocyte syndrome (PLS) Major ABO mismatch: Immediate hemolysis Delayed hemolysis Delayed RBC engraftment/Pure red cell aplasia (PRCA) Bidirectional ABO mismatch: Both features 8

10. Passenger Lymphocyte Syndrome (PLS) 10 Proliferation and antibody production by ?passenger? lymphocytes, which are infused with the stem cell product Rapid onset and may be sever Hemolysis begin 3-15 days after SCT and lasts 5-10 days Incidence: Marrow: 5-10% PBSC: up to 30% Risk factors: No anti-B cell in GvHD PPX regimen (e.g. MTX or MMF) PBSC Donor: URD > Sibiling, No PLS with UCB RIC conditioning Female donor Lab findings: Positive DAT, Donor-derived isohemagglutinin (IH) in serum and eluate Elevated LDH, low hapto, hemoglobulinemia, and hemoglobulinuria Hemolysis usually persists for 5 to 10 days and then subsides as the patient?s residual incompatible red blood cells (RBCs) are destroyed and then replaced by transfused group O RBCs and/or by RBCs of donor type produced by cells derived from the engrafted stem cells. Also, antibody production gradually decreases as the passenger lymphocytes, which are not engrafted, reach the end of their life span. Hemolysis usually persists for 5 to 10 days and then subsides as the patient?s residual incompatible red blood cells (RBCs) are destroyed and then replaced by transfused group O RBCs and/or by RBCs of donor type produced by cells derived from the engrafted stem cells. Also, antibody production gradually decreases as the passenger lymphocytes, which are not engrafted, reach the end of their life span.

11. PLS 11 Figure 1.?Minor ABO-mismatched bone marrow transplant (BMT) (donor group O, recipient B). Flow chart shows hematologic and biochemical evidence for hemolysis. Fourteen units of packed group O RBCs were required to maintain the hemoglobin between day 10 and day 19 post-BMT. Note that hemoglobin, LDH, and total bilirubin levels were normal for the first 5 days post-BMT. During the hemolytic episode, no incompatible isohemagglutinins were infused; RBCs transfused were washed group O, and platelets were group B or washed and resuspended in fresh AB plasma. Reprinted from Hows J, Beddow K, Gordon Smith E, et al: Donor-derived red blood cell antibodies and immune hemolysis after allogeneic bone marrow transplantation. Blood 1986;67:177?181. View Within Article Figure 2.?Flow chart of index group patient not receiving pretransplant exchange transfusion showing transfusion requirements with biochemical and serologic evidence for hemolysis; RBC Tsf, RBC transfusions (arrows); DAT, direct antiglobulin reagent; PS, polyspecific (anti-IgG + C3); IgG, anti-IgG reagent; C3, anti-C3; 4+, cells agglutinated in one clump; 3+, cells agglutinated in three to six very large clumps; 2+ cells agglutinated in many medium clumps; 1+, cells agglutinated in numerous tiny clumps, very cloudy background; +m, very tiny agglutinates only seen microscopically; O, no agglutinates detected; NT, not tested; ?, transfusion. Reprinted from Gajewski JL, Petz LD, Calhoun L, et al: Hemolysis of transfused group O red blood cells in minor ABO-incompatible unrelated-donor bone marrow transplants in patients receiving cyclosporine without posttransplant methotrexate. Blood 1992;79:3076?3085. View Within Article Figure 1.?Minor ABO-mismatched bone marrow transplant (BMT) (donor group O, recipient B). Flow chart shows hematologic and biochemical evidence for hemolysis. Fourteen units of packed group O RBCs were required to maintain the hemoglobin between day 10 and day 19 post-BMT. Note that hemoglobin, LDH, and total bilirubin levels were normal for the first 5 days post-BMT. During the hemolytic episode, no incompatible isohemagglutinins were infused; RBCs transfused were washed group O, and platelets were group B or washed and resuspended in fresh AB plasma. Reprinted from Hows J, Beddow K, Gordon Smith E, et al: Donor-derived red blood cell antibodies and immune hemolysis after allogeneic bone marrow transplantation. Blood 1986;67:177?181.

12. PLS 12 Table 2. Clinical and Laboratory Data Regarding Six Patients Who Received Bone Marrow Transplants From a Minor ABO-Incompatible Donor and Who Developed Hemolytic Anemia in the Post-transplant Period Table 3. Serologic Investigation of Patients Presenting With Immune Hemolysis Table 2. Clinical and Laboratory Data Regarding Six Patients Who Received Bone Marrow Transplants From a Minor ABO-Incompatible Donor and Who Developed Hemolytic Anemia in the Post-transplant Period

13. PLS-PBSC vs. UCB Retrospective analysis of 38 pts with minor ABO incompatible SCT: PBSC: 24 UCB: 14 Hemolysis lab, Donor-derived isohemagglutinin (IH) by reverse ABO grouping Donor-derived IH production: PBSC: 15/24 days 6-88 (mainly days 6-15) 7/15 (50%) showed clinically evident hemolysis, days 7-13 UCB: 0/14 No immune hemolysis 13 Hemolysis lab: drop in Hgb, elevated LDH, bili, decreased hapto, +DATHemolysis lab: drop in Hgb, elevated LDH, bili, decreased hapto, +DAT

14. PLS-MTX 14

15. PLS-BM vs. PBSC 15

16. PLS- Management Monitoring Recipient between days 3-15 Signs of hemolysis, DAT, donor derived Abs (anti-A or anti-B) in patient?s serum or RBC eluate Compatible RBC Avoidance of ABO incompatible plasma products, Adequate renal perfusion Massive hemolysis: Exchange transfusion: replace pt?s Ag+ RBCs with group O RBCS 16 Such supportive care is generally adequate since hemolysis will be selflimiting because newly formed RBCs produced by the donor marrow will not be affected by the donor-derived antibody. Such supportive care is generally adequate since hemolysis will be selflimiting because newly formed RBCs produced by the donor marrow will not be affected by the donor-derived antibody.

17. Minor ABO Mismatch-PLS - Summary 17

18. Major ABO mismatch 18 Potential complications: Immediate hemolysis Delayed RBC engraftment/Pure red cell aplasia (PRCA) Delayed hemolysis

19. Major ABO mismatch-Immediate hemolysis Intravascular hemolysis of the red cells infused with the graft RBC volume in BM product vs. PBCS: BM: > on unit PRBC PBSC: < 10 ml of RBC Were mainly observed in BM-derived SCT Prevention: Removal of ABO-incompatible donor RBCs before infusion of bone marrow derived stem cells 19

20. Major ABO mismatch- delayed engraftment/PRCA RBC engraftment: Independence of RBC transfusion Reticulocyte > 30K/micro L (>1%) Delayed RBC engraftment: RBC engraftment longer than usual Doesn?t fulfill the definition of PRCA Pure red cell aplasia (PRCA): Reticulocytopenia > 60 days after SCT Dependence on RBC transfusions Absence of RBC precursors in bone marrow, Presence of recipient derived IH Abs and exclusion of RBC alloantibodies, viral or bacterial infection, or relapse. Incidence of PRCA: Nonmyeloablative conditioning: 8-38% Myeloablative conditioning: 16-29% 20

21. Major ABO mismatch- delayed engraftment/PRCA 21

22. Major ABO mismatch- delayed engraftment/PRCA 62 patients Sibling: 39 URD: 23 Major ABO incompatible allo-SCT Time to recipient IH disappearance against donor RBC 22 Time to isoagglutinin disappearance against donor-type red blood cells (RBCs). (A) Recipient-derived isoagglutinins against donor-type RBCs disappeared more rapidly after unrelated donor transplantation (solid line) than after sibling donor transplantation (dotted line). Median time to isoagglutinin disappearance was 49 d after unrelated donor transplantation and 166 d after sibling donor transplantation (P ? 0?006, Cox regression). (B) Patients with acute Graft-versus-host disease (GVHD) (solid line) showed more rapid isoagglutinin disappearance against donor-type RBCs than those without acute GVHD after transplantation (dotted line). Median time to isoagglutinin disappearance after transplantation was 56 d in patients with acute GVHD and 175 d in those without acute GVTime to isoagglutinin disappearance against donor-type red blood cells (RBCs). (A) Recipient-derived isoagglutinins against donor-type RBCs disappeared more rapidly after unrelated donor transplantation (solid line) than after sibling donor transplantation (dotted line). Median time to isoagglutinin disappearance was 49 d after unrelated donor transplantation and 166 d after sibling donor transplantation (P ? 0?006, Cox regression). (B) Patients with acute Graft-versus-host disease (GVHD) (solid line) showed more rapid isoagglutinin disappearance against donor-type RBCs than those without acute GVHD after transplantation (dotted line). Median time to isoagglutinin disappearance after transplantation was 56 d in patients with acute GVHD and 175 d in those without acute GV

23. Major ABO mismatch- PRCA vs. Delayed Hemolysis 23

24. Major ABO mismatch- delayed engraftment/PRCA Retrospective analysis of 286 allo-SCT Group 1: ABO compatible ? 167 Group 2: Minor ABO incompatible ? 61 Group 3: Major ABO incompatible ? 58 RBC, PMN, and PLT engraftment: 24

25. Characteristics of patients with PRCA 25

26. PRCA Treatment 26

27. Transfusion in ABO incompatible SCT 27 Note that the selection of fresh frozen plasma (FFP)/platelets is designed to minimize the passive transfer of anti-ABO antibodies that are incompatible with the donor and receipient red blood cell (RBC) antigens. a Recipient has preformed antibodies to donor RBC antigens. b Donor has lymphocytes capable of being stimulated (primary or secondary response) to produce antibodies against recipient RBC antigens. c This type features elements of both major and minor mismatches.Note that the selection of fresh frozen plasma (FFP)/platelets is designed to minimize the passive transfer of anti-ABO antibodies that are incompatible with the donor and receipient red blood cell (RBC) antigens. a Recipient has preformed antibodies to donor RBC antigens. b Donor has lymphocytes capable of being stimulated (primary or secondary response) to produce antibodies against recipient RBC antigens. c This type features elements of both major and minor mismatches.

28. Major ABO mismatch- Delayed Hemolysis 28 Disappearance of donor derived Ab is essential for RBC engraftmentDisappearance of donor derived Ab is essential for RBC engraftment

29. ABO incompatibility effect on survival & GvHD Large retrospective IBMTR study 3103 patients Early-stage leukemia HLA-identical sibling SCT between 1990 and 1998 Myeloablative conditioning Immunosuppression with CSA and MTX The median follow-up: 54 months ABO status: ABO identical : 2108 (67.9%) Minor ABO mismatch: 451 (14.5%) Major ABO mismatch: 430 (13.9%) Bidirectional mismatch: 114 (3.7%) Endpoints: Overall survival, relapse rate, TRM, aGvHD, and cGvHD 29

30. ABO incompatibility effect on survival & GvHD 30

31. ABO incompatibility effect on survival & GvHD 31 Kaplan-Meier survival estimates of overall survival----Cumulative incidence of transplant-related mortality.-----Cumulative incidence of GVHDKaplan-Meier survival estimates of overall survival----Cumulative incidence of transplant-related mortality.-----Cumulative incidence of GVHD

32. Non-ABO Mismatch SCT Rh, Kell, Kidd, MNS, and Lewis systems Potential complications: Passenger lymphocyte syndrome (no sever hemolysis) Delayed hemolysis (in the case of mixed chimerism) No PRCA 32

33. Back to the case 33

34. Summary ABO-incompatible HSCT: 30%-40% Minor ABO mismatch: Recipient has preformed antibodies to donor RBCs Major ABO mismatch: Donor has lymphocytes capable of producing Abs against recipient RBCs Bidirectional ABO mismatch: Features of both major and minor mismatches Minor ABO mismatch can present as PLS: Hemolysis 3-15 days after SCT Major ABO mismatch can present as immediate hemolysis (rare), PRCA, or delayed hemolysis (rare) PRCA can be treated with decreasing immunosuppressant (Graft vs plasma cell), Rituxan (eliminating recipient Ab producing cells), and/or Epo No effect on Overall survival, TRM, relapse rate, and GvHD 34

35. References 1. Stussi et al. Transfusion and Apheresis Science 35 (2006) 59?69 2. Stroncek et al. Transfusion. 1997 Apr;37(4):411-7 3. Petz LD. Semin Hematol. 2005 Jul;42(3):145-55 4. Snell et al. Bone Marrow Transplantation (2006) 38, 135?140 5. Gajewski et al. Blood 1992,79:3076-3085 6. Korbling et al. Blood 1995; 86:2842?2848 7. Yazer et al. Curr Opin hematol. 2007, 14:664-670 8. Worel et al. Transfusion 2000; 40:543-50 9. Blacklock et al. Br J Haematol 1984; 58:267-76 10. Lee et al. Br J of Haematol, 2003, 120, 702?710 11. Seebach et al. Biol Blood Marrow Transplant 2005;11:1006-1013 12. Franchini et al. Bone Marrow Transplantation (2004) 33, 1169?1172 35

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