Year : 2019 | Volume
: 10 | Issue : 2 | Page : 67--69
Desensitization with plasma exchange in a patient with human leukocyte antigen donor-specific antibodies before T-cell-replete haploidentical hematopoietic stem cell transplantation
Rasika Dhawan Setia1, Mitu Dogra1, Divya Doval2, Sanjeev Kumar Sharma2, Dharma Choudhary2, Anil Handoo1,
1 Department of Hematology and Transfusion Medicine, BLK Super Speciality Hospital, New Delhi, India
2 Department of Hemato-Oncology and BMT, BLK Super Speciality Hospital, New Delhi, India
Dr. Rasika Dhawan Setia
Department of Hematology and Transfusion Medicine, BLK Super Speciality Hospital, New Delhi
The presence of human leukocyte antigen (HLA) donor-specific antibodies (DSAs) increases the risk of graft failure in T-cell-replete haploidentical hematopoietic stem cell transplantation (haploidentical-HSCT). We report a case of a 20-year-old male with high-risk thalassemia major who received a haploidentical-HSCT from his mother. Pretransplant recipient screening examination showed positive DSA levels against class I and class II HLAs. The patient underwent a desensitization program consisting of plasma exchange and polyvalent intravenous immunoglobulins. This protocol resulted in the disappearance of DSA class I and reduction in Mean Fluorescence Intensity (MFI) class II antibodies. Engraftment was prompt with stable full donor chimerism. This case report suggests that the adopted scheme is safe for reducing DSA levels and facilitating donor engraftment in patients scheduled for haploidentical-HSCT, though it needs evaluation in a large cohort of patients.
|How to cite this article:|
Setia RD, Dogra M, Doval D, Sharma SK, Choudhary D, Handoo A. Desensitization with plasma exchange in a patient with human leukocyte antigen donor-specific antibodies before T-cell-replete haploidentical hematopoietic stem cell transplantation.J Appl Hematol 2019;10:67-69
|How to cite this URL:|
Setia RD, Dogra M, Doval D, Sharma SK, Choudhary D, Handoo A. Desensitization with plasma exchange in a patient with human leukocyte antigen donor-specific antibodies before T-cell-replete haploidentical hematopoietic stem cell transplantation. J Appl Hematol [serial online] 2019 [cited 2019 Sep 22 ];10:67-69
Available from: http://www.jahjournal.org/text.asp?2019/10/2/67/262544
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) using one human leukocyte antigen (HLA) haplotype-matched first-degree relative donor (haploidentical donor) represents an alternative treatment for patients with hematologic disorders both benign and malignant, who lack HLA-matched related or unrelated donor. Historically, the main limitations of this treatment modality were high rate of graft failure (GF) and graft-versus-host disease (GVHD), which occurs due to intense alloreactive reactions related to the major HLA mismatch between the recipient and the donor. Several approaches have been developed which aimed to partially deplete T-cells in the graft and decrease graft-versus-host alloreactivity. However, GF still remains a major obstacle in major mismatch HSCT. While increased rate of engraftment has occurred with the use of “megadoses” of hematopoietic stem cells (>10 × 106 CD34+ cells/kg with a very low T-cell content [1 × 104 CD3+ cells/kg]), the increased risk of GF following haploidentical-HSCT is due, in part, to enhanced susceptibility of the graft to regimen-resistant host natural killer (NK) cell and T-lymphocyte-mediated rejection against mismatched donor cells. In addition to T-cell and NK-cell-mediated graft rejection (cellular rejection), antibody-mediated rejection (humoral rejection) occurring either by antibody-dependent cell-mediated cytotoxicity or by complement-mediated cytotoxicity has been described. Preformed donor-specific anti-HLA DSAs present at the time of transplant have been shown to correlate with graft rejection and decreased survival in solid organ transplantation., A delay in recognizing this as a major cause of GF in HSCT could be because hematopoietic transplantation has been performed mostly with a high degree of HLA matching between the donor and recipient. The increasing use of mismatched donors (haploidentical, cord blood, and mismatched unrelated donors), in addition to improvements in detection techniques, has facilitated recognizing DSAs as a major cause of graft rejection in HSCT. With the use of highly sensitive solid-phase immunoassays, DSAs were identified in up to 24% of stem cell-transplant recipients.,, Reversal of DSA-mediated graft rejection and reduction in antibody load using plasmapheresis, intravenous immunoglobulin (IVIG), cyclophosphamide, polyclonal anti-lymphocyte antibodies, monoclonal antibodies to CD20+ B-lymphocytes (rituximab), and proteasome inhibitor against alloantibody-producing plasma cells (bortezomib) have been described in solid organ transplant. These treatment modalities are now being tried worldwide to desensitize DSAs in haploidentical-HSCT and mismatched allo-HSCT recipients with a variety of graft outcomes.,,
A 20-year-old male with high-risk class III β-thalassemia major was admitted to undergo a haploidentical-HSCT from his mother in June 2016. Pretransplant recipient screening examination showed DSAs for class I HLA (A*68:01 MFI 4682) and class II (DRB1*11:01 MFI-5464 and DQB1*03:01 MFI 4380) using multianalyte bead assays performed on the Luminex platform. The patient was given fludarabine 40 mg/m2 and dexamethasone 25 mg/m2 for 5 days per month for 2 months. Following this, the patient underwent a desensitization program consisting of polyvalent IVIGs (100 mg/kg) along with serial plasma exchange (PEX) after an informed consent. The patient underwent three cycles of PEX procedures on COM.TEC® cell separator (Fresenius Kabi), using replacement fluid combination of albumin and saline on day − 17, −15, and −13. During each exchange sitting, 1.5 times the plasma volume was exchanged. This protocol resulted in the disappearance of the DSA class I and reduction in MFI for DSA class II (DRB1*11:01 MFI-1042 and DQB1*03:01 MFI-1028).
Conditioning regimen consisted of thymoglobulin, fludarabine, and busulfan. The patient underwent T-cell-replete haploidentical-HSCT using his 43-year-old mother as donor and mobilized peripheral blood as a stem cell source. The hematopoeitic stem cell dose was 11.33 × 106 CD34+ cells/kg body weight of the recipient. GVHD prophylaxis consisted of posttransplant cyclophosphamide, mycophenolate mofetil, and tacrolimus. He had neutrophil engraftment at day +14 and platelet engraftment at day +55. At day +46, he had mild (stage II) acute skin GVHD, which resolved with topical steroids. The patient was discharged on day +100 with a donor chimerism of 98.3%. On follow-up, the patient maintained donor chimerism of 96.93% on day +200 and no Cytomegalovirus (CMV) reactivation. The patient on day 300+ developed fungal (Aspergillus) pneumonitis and was treated with voriconazole 200 mg twice daily. The patient recovered in 3 weeks. On the last follow-up on day 325+, the patient had recovered from skin and liver GVHD and fungal pneumonia. At this time, the patient had 96.5% donor chimerism. Thereafter, the patient went back to his country and is on follow-up with the local transplant physician there.
The degree of HLA matching is important in the setting of HSCT. However, the availability of HLA-identical sibling donors is limited to only one-third of allogeneic-transplant cases. Not all recipients will have a donor complete HLA match. Therefore, other sources of stem cells, including from umbilical cord or HLA-haploidentical family members (alternative donor sources), are being increasingly used. Degree of HLA mismatch varies and is highest in haploidentical transplants. Many potential transplant candidates, especially multiparous women, are HLA allosensitized and the published literature reports HLA DSA rates from a low of 3% to a high of 24%. An increasing volume of outcomes data in alternative donor allo-HSCT patients and animal models suggest that engraftment failure rates are higher in recipients with HLA DSA. Newer approaches of desensitization are being explored including Therapeutic Plasma Exchange/Immunoadsorption (TPE/IA), IVIG, rituximab, and bortezomib to address elevated levels of HLA antibodies. Preformed antibodies present at the time of stem cell infusion are unaffected by standard transplantation conditioning regimens or T-cell or B-cell immunosuppressive or modulatory strategies given in the peritransplantation period.,, The key requirement appears to be sufficient reduction of DSA to prevent antibody-mediated destruction of donor cells before they can engraft. Among the different desensitization regimens, combinations of plasmapheresis with various immunomodulator(s)/immunosuppressant(s) have been most often used and have demonstrated successful DSA reduction. The most popular desensitization protocol for haploidentical-HSCT with positive DSA has been developed by the John Hopkins group, which is different from that used in solid organ transplants, using a combination of repeated plasmapheresis, IVIG, and immunosuppressive medications. This group treated 15 mismatched allo-HSCT patients including 13 Haploidentical Stem Cell Transplants (haplo-SCTs)with alternate day of single volume plasmapheresis followed by 100 mg/kg of IVIG, tacrolimus (1 mg/day, IV), and mycophenolate mofetil (1 g twice daily) starting 1–2 weeks before the beginning of transplant conditioning, depending on patient's starting DSA levels. Reduction of DSA to the level that was thought safe for transplant was seen in 14 of 15 patients, all of these 14 patients engrafted with donor cells. MD Anderson protocol suggests optional use of bortezomib in addition to rituximab and one dose of IVIG and irradiated buffy coat on day − 1 prepared from 1 unit of blood on day − 2 instead of using platelet transfusion to block remaining circulating antibodies after treatment. Compared to John Hopkins and MD Anderson protocols in our case, we neither used bortezomib/rituximab/other immunosuppressant nor used platelets/buffy coat, and we could achieve similar transplant outcome with persistent engraftment. The American Society For Apheresis in their guidelines issued in 2016 has also included hematopoietic stem cell transplant, HLA desensitization, in the list of 14 new diseases where therapeutic apheresis can be beneficial.
This case report suggests that the adopted scheme without bortezomib/rituximab/platelets/buffy coat is safe for reducing DSA levels with low MFI and facilitating donor engraftment in patients undergoing haploidentical-HSCT with successful transplant outcome, though it needs evaluation in a large cohort of patients.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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Conflicts of interest
There are no conflicts of interest.
|1||Ciurea SO, Mulanovich V, Jiang Y, Bassett R, Rondon G, McMannis J, et al. Lymphocyte recovery predicts outcomes in cord blood and T cell-depleted haploidentical stem cell transplantation. Biol Blood Marrow Transplant 2011;17:1169-75.|
|2||Aversa F, Tabilio A, Velardi A, Cunningham I, Terenzi A, Falzetti F, et al. Treatment of high-risk acute leukemia with T-cell-depleted stem cells from related donors with one fully mismatched HLA haplotype. N Engl J Med 1998;339:1186-93.|
|3||Xu H, Chilton PM, Tanner MK, Huang Y, Schanie CL, Dy-Liacco M, et al. Humoral immunity is the dominant barrier for allogeneic bone marrow engraftment in sensitized recipients. Blood 2006;108:3611-9.|
|4||Bramanti S, Nocco A, Mauro E, Milone G, Morabito L, Sarina B, et al. Desensitization with plasma exchange in a patient with human leukocyte antigen donor-specific antibodies before T-cell-replete haploidentical transplantation. Transfusion 2016;56:1096-100.|
|5||Gladstone DE, Zachary AA, Fuchs EJ, Luznik L, Kasamon YL, King KE, et al. Partially mismatched transplantation and human leukocyte antigen donor-specific antibodies. Biol Blood Marrow Transplant 2013;19:647-52.|
|6||Marfo K, Lu A, Ling M, Akalin E. Desensitization protocols and their outcome. Clin J Am Soc Nephrol 2011;6:922-36.|
|7||Ciurea SO, de Lima M, Cano P, Korbling M, Giralt S, Shpall EJ, et al. High risk of graft failure in patients with anti-HLA antibodies undergoing haploidentical stem-cell transplantation. Transplantation 2009;88:1019-24.|
|8||Zachary AA, Lucas DP, Detrick B, Leffell MS. Naturally occurring interference in Luminex assays for HLA-specific antibodies: Characteristics and resolution. Hum Immunol 2009;70:496-501.|
|9||Ishiyama K, Anzai N, Tashima M, Hayashi K, Saji H. Rapid hematopoietic recovery with high levels of DSA in an unmanipulated haploidentical transplant patient. Transplantation 2013;95:e76-7.|
|10||Zachary AA, Leffell MS. Desensitization for solid organ and hematopoietic stem cell transplantation. Immunol Rev 2014;258:183-207.|
|11||Leffell MS, Jones RJ, Gladstone DE. Donor HLA-specific abs: To BMT or not to BMT? Bone Marrow Transplant 2015;50:751-8.|
|12||Kongtim P, Cao K, Ciurea SO. Donor specific anti-HLA antibody and risk of graft failure in haploidentical stem cell transplantation. Adv Hematol 2016;2016:4025073.|
|13||Schwartz J, Padmanabhan A, Aqui N, Balogun RA, Connelly-Smith L, Delaney M, et al. Guidelines on the use of therapeutic apheresis in clinical practice-evidence-based approach from the Writing Committee Of the American Society For Apheresis: The Seventh Special Issue. J Clin Apher 2016;31:149-62.|