Blood 108(8): 2509-2519

Current concepts in the pathophysiology and treatment of aplastic anemia

From the Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health (NIH), Bethesda, MD.

Reprints: Neal S. Young, 10 Center Dr, Bldg 10/CRC, Rm 3E-5140, Bethesda, MD 20892-1202; e-mail: vog.hin.liam@sngnuoy.

Received 2006 Mar 22; Accepted 2006 May 30.

Abstract

Aplastic anemia, an unusual hematologic disease, is the paradigm of the human bone marrow failure syndromes. Almost universally fatal just a few decades ago, aplastic anemia can now be cured or ameliorated by stem-cell transplantation or immunosuppressive drug therapy. The pathophysiology is immune mediated in most cases, with activated type 1 cytotoxic T cells implicated. The molecular basis of the aberrant immune response and deficiencies in hematopoietic cells is now being defined genetically; examples are telomere repair gene mutations in the target cells and dysregulated T-cell activation pathways. Immunosuppression with antithymocyte globulins and cyclosporine is effective at restoring blood-cell production in the majority of patients, but relapse and especially evolution of clonal hematologic diseases remain problematic. Allogeneic stem-cell transplant from histocompatible sibling donors is curative in the great majority of young patients with severe aplastic anemia; the major challenges are extending the benefits of transplantation to patients who are older or who lack family donors. Recent results with alternative sources of stem cells and a variety of conditioning regimens to achieve their engraftment have been promising, with survival in small pediatric case series rivaling conventional transplantation results.

Abstract

Only studies of more than 20 enrolled patients are tabulated. Responses to immunosuppressive therapy are usually partial; blood counts may not become normal but transfusions are no longer required and the neutrophil count is adequate to prevent infection. Relapse is usually responsive to further immunosuppressive therapies. Clonal evolution is to dysplastic bone marrow changes and/or cytogenetic abnormalities. For details, see “Immunosuppression”

In contrast to Table 1, response rates are not provided because, in surviving patients who do not experience primary graft rejection or secondary graft failure, full hematologic recovery with donor hematopoiesis is anticipated. Only studies reporting at least 20 patients are tabulated

GVHD indicates graft-versus-host disease; IBMTR, International Blood and Marrow Transplant Registry; and EBMT, European Group for Bone Marrow Transplant

Only studies reporting at least 5 patients are tabulated. GVHD, graft-versus-host disease; IBMTR, International Blood and Marrow Transplant Registry; MUD, matched unrelated donor; MMUD, mismatched unrelated donor; Cy, cyclophosphamide; ATG, antithymocyte globulin; TBI, total body irradiation; CP, alemtuzumab; LFI, limited field irradiation; TCD, T-cell depletion; TLI, total lymphoid irradiation; Flu, fludarabine; UCB, umbilical cord blood; MMRD, mismatched related donor; and TT, thiotepa

Acknowledgments

We are thankful to colleagues from the Hematology Branch, Drs A. John Barrett, Cynthia Dunbar, Richard Childs, and Elaine Sloand, and in Europe, Professors Judith Marsh, Gérard Socié, and André Tichelli for their careful reading of the paper and helpful criticisms.

The authors apologize to their colleagues whose papers were not cited in the bibliography due to space constraints.

Acknowledgments

Notes

Prepublished online as Blood First Edition Paper, June 15, 2006; DOI 10.1182/blood-2006-03-010777.

Supported by NIH Intramural Research program.

N.S.Y. wrote “Introduction” and “Etiologies” as well as contributed to “Pathophysiology” and “Treatment”; R.T.C. wrote “Pathophysiology”; and P.S. wrote “Treatment.” All authors contributed to the final paper.

Notes

Prepublished online as Blood First Edition Paper, June 15, 2006; DOI 10.1182/blood-2006-03-010777.

Supported by NIH Intramural Research program.

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