Mini Transplants Provide Benefit in Patients w/ CLL Who Have Stopped to Fludara®

According to results presented at the 42nd annual meeting of the American Society of Clinical Oncology (ASCO), mini allogeneic stem cell transplants appear to provide significant benefit in patients with chronic lymphocytic leukemia who have stopped responding to standard therapies, including the chemotherapy agent Fludara® (fludarabine).

Chronic lymphocytic leukemia (CLL) is the most common form of adult leukemia, affecting approximately 120,000 people in Europe and the U.S. The disease is most commonly diagnosed among people age 50 or older.

Leukemias are cancers that affect cells of the immune system. CLL is a type of leukemia that is considered slow-growing and is referred to as low-grade leukemia. If a patient stops responding to standard therapies, they have what is called refractory leukemia. Optimal treatment for refractory CLL continues to be evaluated to provide optimal long-term survival for this group of patients. High-dose chemotherapy and an allogeneic stem cell transplant may achieve long-term survival in these groups of patients; however, mortality related to allogeneic stem cell transplant keeps a large portion of patients from undergoing the procedure.

High-dose chemotherapy kills more cancer cells than standard chemotherapy; however, it also causes more damage to the blood cells, particularly those in the bone marrow. The bone marrow (and circulating blood) contains early blood-forming cells called stem cells, which grow and mature into three blood cell types: white blood cells, which protect the body from infection; red blood cells, which carry oxygen to the tissues; and platelets, which help the blood to clot. When bone marrow is destroyed, stem cells are depleted, leading to low levels of circulating blood cells. When these cells reach critically low levels, potentially fatal complications-such as anemia, bleeding, and infection-can occur. Thus, it is critical to restore stem cell levels as quickly as possible.

A stem cell transplant is a procedure that replaces the stem cells that are destroyed by high-dose chemotherapy with healthy stem cells, thereby allowing more rapid recovery and production of the red blood cells, white blood cells, and platelets. During an autologous stem cell transplant, stem cells that were collected directly from the patient prior to the delivery of the high-dose chemotherapy are re-infused following treatment. In contrast, an allogeneic stem cell transplant involves stem cells collected from a donor. In addition to the anticancer effect of the high-dose therapy, an allogeneic stem cell transplant induces a second anticancer effect called graft-versus-leukemia effect. In this process, which occurs after an allogeneic transplant, the presence of the foreign donor stem cells (i.e., the graft) stimulates the immune system to attack the remaining cancer cells.

Unfortunately, standard allogeneic stem cell transplant regimens have been associated with a high treatment-related mortality rate in patients with CLL. In addition, many patients suffer from chronic treatment-related causes, including graft-versus-host disease. Graft-versus-host disease (GVHD) is an attack on the patient’s healthy tissues by the donor lymphocytes and can be either acute or chronic.

Recently, researchers have developed treatment strategies that take advantage of the graft-versus-leukemia effect while attempting to reduce complications caused by the transplant procedure. One strategy being evaluated involves the use of lower doses of chemotherapy and/or radiation therapy followed by an allogeneic stem cell transplant, called a mini-transplant, a non-myeloablative transplant, or a reduced intensity allogeneic stem cell transplant. At present, there is very little data evaluating this treatment approach in low-grade refractory cancers affecting blood cells, such as leukemia.

Researchers from the Fred Hutchinson Cancer Research Center recently reported updated outcomes from a trial including patients with refractory CLL. This trial included 64 patients; over 80% had stopped responding to the commonly used chemotherapy agent Fludara; 25% had stopped responding to treatment with Rituxan® (rituximab), and 30% stopped responding to chemotherapy agents referred to as alkylating agents.

Patients were treated with a mini allogeneic stem cell transplant. Forty-four patients received stem cells from a related donor, and 20 patients received stem cells from an unrelated donor. The patients in this trial were either elderly or had significant additional medical conditions that made them ineligible for high-dose therapy and a stem cell transplant.

The follow-up of these patients had been between three and four years.

  • Complete disappearances of cancer remaining at three years following treatment is 44% for those treated with stem cells from a related donor, compared with 80% for those treated with stem cells from an unrelated donor.
  • At three years, cancer-free survival is 37% for those who received stem cells from a related donor and 51% for those who received stem cells from an unrelated donor.
  • At three years, the overall survival rates are 48% for those who received stem cells from a related donor and 68% for those who received stem cells from an unrelated donor.

The researchers concluded that mini allogeneic stem cell transplants, particularly those including an unrelated donor of stem cells, provide encouraging cancer-free survival at three years following the procedure for patients with refractory CLL. Future trials will continue to evaluate mini transplants in this patient population.

Reference: Sorror M, Sandmaier B, Maris M, et al. Nonmyeloablative hematopoietic cell transplantation (HCT) for treatment of patients (pts) with fludarabine refractory chronic lymhocytic leukemia (CLL) results in prolonged median survival. Proceedings from the 42nd annual meeting of the American Society of Clinical Oncology. Atlanta, Ga. 2006. Abstract # 6620.

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