Case Report

Pseudoautologous blood stem cell transplantation for refractory chronic graft-versus-host disease

  • Bone Marrow Transplantation 29, 709710 (2002)
  • doi:10.1038/sj.bmt.1703550
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A female patient with AML received an allogeneic BMT from her brother. She experienced two relapses managed with chemotherapy and donor leukocyte infusions. The patient subsequently developed extensive therapy-refractory chronic GVHD. Pseudoautologous blood stem cell transplantation was performed as a salvage treatment for chronic GVHD. Her blood stem cells were easily mobilized with cyclophosphamide and G-CSF. The conditioning regimen was well tolerated and consisted of 200 mg/kg cyclophosphamide and horse-derived antithymocyte globulin. A total of 4.03 × 106/kg CD34+ cells were infused and hematological recovery was rapid. Chronic GVHD improved with the ability to taper steroids. Nine months post transplantation the patient died from leukemia.


A 23-year-old white female was diagnosed with acute myeloid leukemia AML-M2 in April 1994, her bone marrow cytogenetics showed monosomy of chromosome seven. In first remission the patient underwent allogeneic bone marrow transplantation from her HLA-identical brother. During 1995, the patient was treated twice for AML relapse using cytarabine-based chemotherapy followed by infusion of G-CSF mobilized donor leukocytes. During the subsequent 3 years she suffered from recurrent chronic graft-versus-host disease (cGVHD) of the skin, mouth, liver and eyes. Skin biopsy confirmed the diagnosis of cGVHD. She was treated with steroids, cyclosporine, extracorporeal photopheresis (Uvadex; Therakos, Exton, PA, USA), azathioprine, acitretin, and low-dose oral cyclophosphamide. Her symptoms waxed and waned with transient improvement or stability, but the cGVHD ultimately became refractory to all treatments. In spring 1998, despite repetitive pulses of methylprednisolone 200 mg/day and addition of cyclophosphamide 50 mg/day, and azathioprine 50 mg/day, the cGVHD progressed relentlessly. Her lower extremities exhibited extensive sclerodermatous changes spreading up to the groin with nodularity, ulcerations and loss of hair. Movements in her ankles were restricted and her buttocks were painful. Arms were affected with plaque-like lesions. Her oral mucosa showed lichen planus-type lesions and altered topography of the tongue, and her eyes had conjunctival injection. Alkaline phosphatase and transaminase were moderately elevated. With the disease progression, she stopped working and developed depression receiving sertraline for relief. The Karnofsky score was 60%.

In June 1998, an ablation of her immune system with high-dose cyclophosphamide followed by pseudoautologous blood stem cell rescue was attempted. The Institutional Review Board approved the protocol and written informed consent was obtained from the patient. She received one dose of cyclophosphamide 2 g/m2 i.v. followed by G-CSF 10 μg/kg/day s.c. starting on day 5 for mobilization of hematopoietic stem cells. Three 15-liter leukaphereses (COBE, Lakewood, CO, USA) were performed on days 11, 12 and 13, and a total of 4.03 × 106/kg CD34+ cells, 5.9 × 108/kg mononuclear cells and 47.2 × 104/kg CFU-GM were obtained. Prior to mobilization, her bone marrow biopsy showed normocellular bone marrow with trilineage hematopoiesis and no dysplastic changes. After an 8-day rest, the patient started a conditioning regimen with cyclophosphamide 50 mg/kg/day i.v. days −5 to −2 (total dose 200 mg/kg) and horse-derived antithymocyte globulin (ATG) 20 mg/kg/day i.v. days −3 to +3 (except day 0). Post-transplant, she was given G-CSF 5 μg/kg/day s.c. until neutrophil recovery. Infection prophylaxis included cefepime, sulfametoxazole/trimethoprim, fluconazole and acyclovir. Hematologic recovery was rapid; neutrophils were >0.5 × 109/l on day +8, and platelets were >50 × 109/l on day +12. The patient required two transfusions of irradiated platelets and no red blood cells. Prior to each dose of ATG, the patient received methylprednisolone 2 mg/kg i.v. until day +3 when it was replaced with oral prednisone. Intravenous cyclosporine 50 mg i.v. every 12 h was administered during the transplantation procedure and continued orally thereafter at 100 mg twice per day. Immediately after transplant her oral mucosa was clear, her eyes were noninjected, and the sclerodermatous changes regressed with more flexibility in her ankles. About day +18 new areas of skin erythema developed along with recurrent ulcerations and stiffness of her extremities. Lichenoid oral lesions and changes of her tongue recurred, but were less severe than pre-transplant. Liver enzymes were normal. Acitretin and photopheresis were restarted to maintain the response. During the next 3½ months, although she was noncompliant in taking cyclosporine, her symptoms were stable and after the addition of azathioprine, the prednisone dose was tapered to less than 10 mg/day. The skin was much softer, without erythema and she could perform nearly full extension and flexion of her ankles. Sclerodermatous changes of her arms nearly resolved and the oral lesions remained stable. She was able to return to her full-time job. Karnofsky performance status at that time was 80%. A routine bone marrow biopsy in December 1998 showed leukemic relapse, this time of a different AML type-M7 and no evidence of original clone. In situ bone marrow cytogenetics demonstrated leukemic blasts of female origin. The patient died after 3 months of progressive leukemia.


High-dose chemotherapy followed by autologous peripheral blood stem cell transplantation (autoBSCT) has been recently proposed as a treatment for refractory autoimmune diseases.1,2,3 Chemotherapy at immunoablative doses is intended to eliminate autoreactive lymphocyte clones or to interrupt autoimmune regulatory circuits. Reinfusion of stem cells for hematopoietic rescue is also intended to reconstitute a new immune system that may be ‘naive’ and immunologically tolerant towards putative autoantigens. Among autoimmune disorders, scleroderma is one of the most commonly treated with autoBSCT.2,4 In cGVHD, T cells produce cytokines that stimulate fibroblast proliferation and collagen production resulting in skin changes that resemble scleroderma.5 The patient presented here was treated on a protocol that was originally designed for patients with refractory rheumatoid arthritis, reasoning an autoimmune pathophysiology of cGVHD.6,7

We called this transplant ‘pseudoautologous’ since her hematopoietic system was largely comprised of her donor's cells. Stem cell mobilization was conducted with ease and post-transplant recovery was uneventful in spite of multiple prior therapies, significant co-morbidity, and impaired performance status. After the transplant, while cGVHD persisted, it was less severe. The patient required reduced immunosuppressive therapy. Perhaps cGVHD persisted because the preparative regimen was not sufficiently immunoablative and more vigorous lymphoablative therapies might have provided a better outcome. Residual autoreactive or alloreactive lymphocytes present in the stem cell harvest could also have been responsible for the recurrence of cGVHD.8 In contrast to animal models of autoimmunity, however, it is uncertain whether graft manipulation and lymphocyte depletion are beneficial in clinical transplantation for autoimmune diseases. Additionally, aggressive removal of T and B cells may delay immunologic recovery and increase the risk of opportunistic infections.

In the patient described here, cyclosporine was continued to prevent cGVHD. Cyclosporine during autoBSCT can induce a systemic autoimmune syndrome clinically and histopathologically similar to GVHD after allogeneic bone marrow transplantation.9 Whether this influenced cGVHD activity post transplant is unclear. The transient improvement noted early in the patient's post-transplant course could have been related directly to immunosuppression produced by the high-dose regimen, ATG, and high-dose steroids, as described in patients with autoimmune disorders.3 However, later stability of cGVHD and the ability to taper steroids after reintroducing previously ineffective immunosuppressive therapy could have been a consequence of an immunological environment changed during immunological reconstitution.10 Patients with rheumatoid arthritis who relapsed after autoBSCT have responded well to medication which were previously ineffective.6 The immunoablative regimen and immunosuppression may have diminished the graft-versus-leukemia effect contributing to leukemia relapse. Experience from this case suggests that mobilization of hematopoietic progenitors and pseudoautologous blood stem cells transplantation are feasible in patients with refractory cGVHD. Optimal timing and indication for this mode of therapy should be analyzed in the context of other therapeutic options for cGVHD. Future studies of such transplantation may require different transplantation regimens.


  1. 1.

    , , et al. Autologous hematopoietic stem cell transplants for autoimmune disease-feasibility and transplant-related mortality Bone Marrow Transplant 1999 24: 729 734

  2. 2.

    , , et al. High-dose immunosuppressive therapy (HDIT) and autologous stem cell transplantation for severe systemic sclerosis (SSc) Blood 2000 96: 844a

  3. 3.

    , , et al. Treatment of autoimmune disease by intense immunosuppressive conditioning and autologous hematopoietic stem cell transplantation Blood 1998 92: 3505 3514

  4. 4.

    , , et al. Phase I/II trial of autologous stem cell transplantation in systemic sclerosis: procedure related mortality and impact on skin disease Ann Rheum 2001 60: 577 584

  5. 5.

    , , et al. Cytokine expression in human cutaneous chronic graft-versus-host disease Bone Marrow Transplant 1996 17: 1085 1092

  6. 6.

    , , et al. Intensive immunoablation and autologous blood stem cell transplantation in patients with refractory rheumatoid arthritis: The University of Nebraska Experience J Rheumatol 2001 28: (Suppl. 64) 13 20

  7. 7.

    . Chronic graft-versus-host disease Curr Opin Hematol 1998 5: 22 25

  8. 8.

    , , et al. Immunoablative high-dose cyclophosphamide without stem-cell rescue for refractory, severe autoimmune disease Ann Intern Med 1998 129: 1031 1035

  9. 9.

    , , et al. Clinical course and predictive factors for cyclosporine-induced autologous graft-versus-host disease after autologous hematopoietic stem cell transplantation Br J Haematol 2000 111: 745 753

  10. 10.

    , , . Immune reconstitution and immunotherapy after autologous hematopoietic stem cell transplantation Blood 1998 92: 1471 1490

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Author information


  1. University of Nebraska Medical Center, Department of Internal Medicine, Section of Oncology and Hematology, Omaha, NE, USA

    • I Pusic
    • , SZ Pavletic
    • , A Kessinger
    • , SR Tarantolo
    •  & MR Bishop
  2. National Cancer Institute, Department of Experimental Transplantation and Immunology, National Institutes of Health, Bethesda, MD, USA

    • MR Bishop


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Corresponding author

Correspondence to SZ Pavletic.