Q&A: Intravenous busulfan before stem cell transplant

The invention of IV Busulfex™ (the intravenous formulation of busulfan) has contributed to a dramatic change in the standard of care for patients undergoing stem cell transplantation for leukemia. It also has greatly improved the outlook for patients with hematologic (blood) and lymphoid cancers.

In March, the lead inventor, Borje S. Andersson, M.D., Ph.D., professor in MD Anderson's Department of Stem Cell Transplantation and Cellular Therapy, was honored with the 2010 Chancellor's Entrepreneurship and Innovation Award from The University of Texas System. He answers questions about this pre-transplant treatment development that has now received regulatory approval for use in 45 countries, with the drug available on a limited basis in an additional three countries.

What is IV busulfan?
IV busulfan is a chemotherapy agent, given to patients intravenously in combination with other drugs, commonly cyclophosphamide, or Fludara™ (fludarabine) or Clolar™ (clofarabine) before they have a stem cell transplant. In 1999, the U.S. Food and Drug Administrations approved IV busulfan for use in chronic myelogenous leukemia (CML) patients undergoing stem cell transplantation.

Why is it combined with other drugs?
Busulfan is one of our most potent anti-leukemia drugs. It's also very toxic to the normal bone marrow cells, but it's not very immunosuppressive. Therefore, it was originally combined with the immunosuppressive drug cyclophosphamide to get the new stem cells to engraft. Because this combination has serious side effects, the cyclophosphamide was later replaced with fludarabine, which is strongly immunosuppressive.

The fludarabine-busulfan combination has proven most effective, especially when used in patients with early leukemia (patients in remission). Using IV busulfan in this combination has dramatically increased the safety of the transplant procedure. The risk of dying from complications during the first 100 days after transplant has come down from about 30%-40% to about 3%, and the chance of being alive and doing well at three to five years after transplant has gone up from about 40% to about 75%, if done in first or second remission of acute leukemia.

For patients with active acute myelogenous leukemia (AML) -- especially when unresponsive to regular chemotherapy -- we're now investigating if a combination of fludarabine and its cousin clofarabine is more effective when given together with IV busulfan than when fludarabine alone is used with busulfan. The early data favor the gradual replacement of fludarabine with clofarabine or, even better, using both fludarabine and clofarabine together with busulfan in this setting.

Why is busulfan so effective before stem cell transplants?
Patients with AML and CML often have high white blood cell counts, and these leukemic cells suppress the production of normal blood cells. Busulfan acts directly on the DNA and indiscriminantly kills both normal and abnormal blood cells -- lowering the patient's white blood cell count -- while having very limited toxicity to organs other than the bone marrow. This makes it ideal for use before a stem cell transplant.

If you have too many abnormal white blood cells, the body has a higher risk of rejecting the transplant. The IV busulfan lowers the number of white blood cells, and with the added immunosuppression of fludarabine, rapidly enables the graft to start growing in the recipient.

For which types of cancer is it most effective?
At MD Anderson, IV busulfan combined with fludarabine is now the standard pre-transplant therapy for patients with AML and myelodysplasia syndrome (MDS), as well as for CML. It's also used for patients with myeloproliferative disorders and myelofibrosis, and for certain lymphomas and Hodgkin's disease.

Can it be used for children as well as adults?
IV busulfan is gradually replacing total body radiation as pre-transplant "conditioning" treatment for both pediatric and adult patients. This is especially important in children because total body radiation affects physical and mental development.

While physical retardation can be partly addressed with growth hormones, cognitive dysfunction can be as much as 20 points lower than for healthy peers when compared in IQ testing.  Further, total body irradiation is fraught with a significant risk for late development of secondary cancers, such as breast cancer, which is most important when pediatric patients are cured of their initial leukemia.

What comes next?
We've gone back to the laboratory to gain a better understanding of the molecular mechanisms that are at work here. While patients' cancers go into remission initially, many relapse, sometimes as early as within the first few months. We want to know why so we can further increase the effectiveness of our pre-transplant therapy and use these mechanisms to fight the cancer rather than just observe how the cancer gets back in the driver's seat.