Stem cell transplantation in Acute Myeloid Leukemia

Once diagnosed, the survival rate of patients with acute myeloid leukemia (AML) is low: Two-thirds of young adults and 90% of older adults still die of their disease and its sequelae. Although there has been considerable progress in the treatment of AML in recent years, it is clear that there is still an urgent need for improvement

Allogeneic stem cell transplantation (SCT) is regarded as the single most effective treatment for preventing relapse in AML patients in complete remission after induction therapy.

Moreover, allogeneic SCT has a significant survival benefit for intermediate- and poor-risk AML patients in first complete remission (CR1).

Complications of allogeneic SCT

Major complications associated with allogeneic SCT are acute and chronic graft-versus-host disease (GVHD), both caused by the presence of donor T cells in the graft. Depending on the severity, GVHD can be associated with increased morbidity and mortality following transplantation.

Acute GVHD: A short-term complication

The risk of acute GVHD following allogeneic transplantation from HLA matched sibling donors is between 20% and 60% despite the use of immunosuppressive agents, such as cyclosporin A, tacrolimus, methotrexate, antithymocyte globulin and corticosteroids alone or in combination. Grade II-IV (moderate to severe) acute GVHD is associated with an increased risk of transplant-related mortality. Mortality rates among patients who develop severe GVHD can be as high as 75% if the disease does not respond to immunosuppressive therapy.

Chronic GVHD: A severe long-term complication

Chronic GVHD is the most serious and common long-term complication of allogeneic SCT. It occurs in 30% to 70% of adults and children who survive more than 100 days post transplantation. Approximately half of affected patients have three or more involved organs, and treatment typically requires immunosuppressive medications for a median of two to three years. In a subset of patients treatment is often prolonged, with 15% receiving immune suppressive therapies seven or more years after the initial diagnosis of chronic GVHD. The morbidity and mortality associated with chronic GVHD is caused both by chronic GVHD-associated immunodeficiency and organ dysfunction and by the immune suppressive medications used to treat it

A chronic GVHD diagnosis is strongly correlated to poor quality of life, attributable to impairment of multiple organs, and/or the occurrence of secondary malignancies. Despite a variety of pharmacologic approaches, treatment of chronic GVHD remains unsatisfactory. Corticosteroids are the mainstay of therapy, but they are not always effective and their long-term use leads to multiple complications. Moreover, it has been suggested that chronic GVHD observed following peripheral blood stem cell transplantation may be more difficult to treat and require a greater duration of corticosteroid use in comparison to bone marrow. This results in a higher risk of late complications.

Therefore, the goal of allogeneic stem cell transplantation in AML is to achieve disease free survival in the absence of acute and chronic GVHD.

Allogeneic SCT for the high-risk AML patient

Many studies have shown that removing T cells from the donor graft by positive enrichment of CD34+ hematopoietic stem cells before transplantation effectively prevents GVHD. But, concerns about the potential risks of graft rejection, relapse and survival have limited the level of acceptance of this important therapeutic modus. There has, however, been a number of publications involving patients with AML that suggest a low risk of GVHD and relapse with this technology, particularly in patients transplanted in remission.