Priorities for Improving Outcomes for Nonmalignant Blood Diseases
TRIALS TO IMPROVE OUTCOMES FOR NONMALIGNANT BLOOD DISORDERS
Bone marrow failure disorders, either acquired or inherited, are primarily characterized by inadequate production of neutrophils, red blood cells, and/or platelets, although other organs may be involved. Allogeneic HCT is an effective treatment for these conditions and many are the only known cure. Historically, patients with certain inherited bone marrow failure diseases have had poor outcomes following HCT using conventional myeloablative approaches (myeloablative conditioning [MAC]) such as busulfan combined with cyclophosphamide or total body irradiation (TBI)-based regimens. While these regimens result in high rates of engraftment, they also come with increased risk for transplant-related morbidity and mortality from complications such as sinusoidal obstructive syndrome. As a result, less intense regimens have been investigated. These less intense regimens, however, carry an increased risk for graft rejection, particularly in patients with competent immune systems and/or normocellular marrows who may require higher intensity conditioning to overcome these barriers to engraftment. Prospective studies are needed to develop less toxic conditioning regimens that are effective at establishing long-term multilineage engraftment.
Treosulfan is a prodrug of an alkylating agent structurally related to busulfan but with a different mode of alkylation. Treosulfan has both cytotoxic and immunosuppressive properties and has been increasingly used as the backbone of HCT conditioning regimens in both pediatric and adult patients with hematologic malignancies and nonmalignant diseases, primarily in the European Union. Treosulfan has characteristics that make it particularly appealing for use in HCT. One particularly encouraging characteristic is that it is water-soluble and bypasses hepatic enzyme activation and as a result has been associated with a low incidence in sinusoidal obstructive syndrome. A phase II prospective study of treosulfan combined with fludarabine § rabbit anti-thymocyte globulin (ATG) in 23 patients with bone marrow failure disorders resulted in 2-year overall and event-free survival of 96% with a low incidence of acute grade II to IV (39%) and grade III to IV (4%) and National Institutes of Health (NIH) chronic (9%) GVHD. The 1-year GVHD-free, event-free survival (EFS) was 87%. There were no graft rejections. A follow-up report of this regimen in a subset of 14 patients with bone marrow failure disorders revealed highly similar outcomes.
b-Thalassemia major is severe anemia caused by mutations in the b-globin gene. Patients with thalassemia require lifelong blood transfusions, which predisposes them to iron overload and associated organ-specific dysfunction. Allogeneic HCT is currently the only established curative therapy for transfusion-dependent thalassemia leading to transfusion independence, resolution of iron burden, and long-term disease-free survival ranging from 78% to 81% [17,18]. Transplant-related mortality (TRM), often tied to chronic iron overload, is a barrier to increased utilization of allogeneic HCT as a curative therapy. The best-reported outcomes are with HLA-matched sibling donors. However, only 30% of children in need of a BMT have an HLA-identical family member, and
well-matched alternative donors are often not available.
There have been several recent attempts to improve outcomes after allogeneic HCT using alternative donors. The use of bone marrow or cord blood stem cells from unrelated donors following a reduced-intensity conditioning (RIC) regimen in 33 patients was accompanied by significant rates of acute and extensive chronic GVHD. Moreover, 6 patients died of transplant-related toxicity or viral reactivation. Myeloablative conditioning using related or unrelated donors and augmented GVHD prophylaxis with abatacept or maraviroc in 13 patients resulted in low mortality but chronic GVHD and viral reactivation rates remained high. Thus, efforts to extend the curative potential of allogeneic HCT through the use of alternative donors has been associated with both significant GVHD and treatment failure rates of 20% to 30%. The use of haploidentical donors after MAC has produced mixed results. Depletion of ab-T cell receptor cells and CD19 cells from stem cell grafts was still associated with graft failure, extensive chronic GVHD, post-HCT lymphoproliferative disease, and delayed immune reconstitution. By contrast, the use of haploidentical donors, pre-HCT immune suppression with fludarabine/dexamethasone, full-intensity conditioning, and postHCT cyclophosphamide (PT/Cy) for GVHD prophylaxis resulted in 100% engraftment and 94% overall survival in 31 patients. While this regimen showed promise, it required extensive pre-HCT immune suppression and exposes young patients to the long-term sequelae of myeloablative conditioning. New strategies to achieve long-term disease-free survival without unacceptable GVHD rates or exposure to myeloablative chemotherapy are still needed.
Hemophagocytic lymphohistiocytosis (HLH) is an inherited or acquired syndrome characterized by immune dysregulation and pathologic inflammation. The hallmark of this disorder is the overproduction of interferon-gamma (IFNg) from dysfunctional T cells. HLH is most often diagnosed in children but can also occur in adulthood. Allogeneic HCT is curative when the underlying cause is due to intrinsic defects in immune function, although in some cases, no genetic mutation is identified. Familial HLH is typically associated with pathogenic variants in genes such as PRF1, UNC13D, STX11, and STXBP2 that regulate NK and T cell cytotoxicity. Immune dysregulation from primary immune deficiencies and inflammasome disorders may also drive the clinical manifestations. HLH is a
challenging condition to transplant due to the high incidence of infection, organ dysfunction, and active inflammation/immune dysregulation pre-HCT. As a result, HCT recipients are at high risk for both TRM and graft rejection. Three-year overall survival with MAC was only 43%. A novel RIC regimen combined alemtuzumab on to immunoblot the host and decrease graft rejection with moderate-dose fludarabine and melphalan to decrease TRM. In a single-center pediatric review of 26 patients receiving RIC and 14 patients receiving MAC, 3-year survival was improved to 92%, but 65% of patients developed mixed chimerism and required immunologic maneuvers, including additional retransplant. The BMT CTN tested this RIC regimen in 46 patients (HLH, n = 34; other primary immunodeficiency disorders, n = 12) in a multicenter study. Overall survival at 1 year was 80%, but only 39% of patients experienced sustained engraftment without donor leukocyte infusion or second HCT. New strategies to improve long-term engraftment are needed.
Author: John E. Levine1, Joseph H. Antin, Carl E. Allen, Lauri M. Burroughs, Kenneth R. Cooke, Steven Devine, Helen Heslop, Ryotaro Nakamura, Julie An Talano, Gregory Yanik11, Nancy DiFronzo