Priorities for Improving Outcomes for Nonmalignant Blood Diseases: A Report from the Blood and Marrow Transplant Clinical Trials Network

Nonmalignant blood diseases such as bone marrow failure disorders, immune dysregulation disorders, and hemoglobinopathies often lead to shortened life spans and poor quality of life. Many of these diseases can be cured with allogeneic hematopoietic cell transplantation (HCT), but patients are often not offered the procedure because of perceived insufficient efficacy and/or excess toxicity.

The Blood and Marrow Transplant Clinical Trials Network (BMT CTN), which is funded by the National Heart, Lung, and Blood Institute and the National Cancer Institute, is uniquelypositioned to strategically prioritize and address these concerns. The BMT CTN includes 20 core centers and consortia that collectively transplant nearly 10,000 patients per year.

The resulting size and scope of the network is sufficient to conduct clinical HCT trials even in the rarest of diseases. In 2018, the BMT CTN formed a task force to identify the most urgently needed yet feasible clinical trials with potential to improve the outcomes for patients with nonmalignant diseases.

The task force followed the previously successful format used in State of the Science Symposia that set the scientific priorities of the BMT CTN twice in the past. A task force of 8 members and a chair was formed from the 20 BMT CTN core and consortia centers with the final composition intended to maximize diversity of viewpoints and expertise. Proposals were solicited from all members, and each proposal was reviewed and critiqued by 2 task force members prior to discussion during weekly webinars. Proposals were broadly divided into 2 categories.


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 effective treatment for these conditions and for many is 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.

Transfusion-Dependent Thalassemia

b-Thalassemia major is a 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%.

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.

Hemophagocytic Lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is an inherited or acquired syndrome characterized by immune dysregulation and pathologic inflammation. The hallmark of this disorder is 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 days to immunoablate 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.

Gene Therapy for b-Hemoglobinopathies

b-Thalassemia and SCD are the world’s most widely disseminated hereditary hemoglobinopathies. Despite better medical therapies such as effective chelation for iron overload, prediction of stroke risk, and hydroxyurea to decrease vaso-occlusive crises (VOCs) in SCD, individuals with severe disease require numerous blood transfusions, are frequently hospitalized, and have early mortality.

Allogeneic HCT offers the potential for cure, but as noted above, current rates of toxicity and lack of suitable donors limit its applicability. A strategy to improve upon current allogeneic HCT results for transfusion-dependent thalassemia is a high-priority proposal from this task force. Gene therapy for these monogenic disorders is another approach.

Recently, lentiviral vectors have been used to introduce a modified beta hemoglobin gene into autologous hematopoietic stem cells, which have restored adult hemoglobin production in the first gene therapy trials for b-thalassemia and SCD. Preclinical and early phase clinical studies have shown preliminary efficacy and safety.

Transplantation of autologous CD34+ cells transduced with the lentiviral vector reduced or eliminated the need for long-term red blood cell transfusions in 22 patients with severe b-thalassemia without any serious adverse events related to the drug product. A second trial showed persistent engraftment of vector-marked cells in hematopoietic progenitors without clonal dominance. Transfusion requirements were reduced in both adults and children.


Bronchiolitis obliterans syndrome (BOS) is a chronic obstructive airway disease that occurs in 5% to 12% of allogeneic HCTs. The disorder is characterized by progressive fibro-obliteration of terminal bronchioles, with resultant air trapping, progressive dyspnea, recurrent pulmonary infections, and an overall decrease in quality of life. Inhaled steroids, such as fluticasone, may stabilize symptoms, but survival following the development of BOS is only 20% to 40%.

The criteria used to define BOS are strict and limit the diagnosis to patients who already have developed severe airflow obstruction, when irreversible fibro-obliterative changes in the lungs have likely already occurred. Earlier intervention is needed to improve outcomes. BOS 0p is a spirometric parameter defined by a >10% decline in forced expiratory volume in 1 second (or >25% decline in FEF25-75) on consecutive pulmonary function tests.

BOS 0p has high sensitivity in predicting BOS development in lung transplant recipients and was recently shown to be an independent predictor of BOS in allogeneic HCT recipients. The presence of more than 1 risk factor for BOS increases the likelihood of a poor outcome.

Cardiovascular Disease in HCT Survivors

Advances in HCT have led to a 10% improvement in survival each decade since the 1980s, resulting in an estimated 200,000 HCT survivors alive in the United States today. Despite these improvements, HCT survivors continue to have substantially higher mortality rates compared with the general population. In particular, the risk of cardiovascularrelated mortality is more than twice that of the general population, and the magnitude of risk increases with time from HCT.

However, examining cardiovascular-related mortality alone underestimates the true burden of cardiovascular morbidity. HCT survivors have a 4-fold higher risk of developing cardiovascular disease (CVD) compared with the general population, adding to the already high burden of chronic health-related conditions in these survivors. It has been increasingly recognized that aggressive monitoring and management of CVD risk factors can result in clinically significant reduction in future cardiovascular events.

For example, in patients with hypertension, a management strategy with a goal systolic blood pressure of <140 mm Hg may not be as effective as trying to achieve lowest feasible/tolerable systolic blood pressure to reduce future CVD risks. At present, there are no established evidence-based targeted interventions to reduce CVD risk after HCT, due to the paucity of information on appropriate risk stratification after HCT.

Author: John E. Levine, Joseph H. Antin, Carl E. Allen



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