"Mini-transplants"

The field of bone marrow transplantation has been undergoing dramatic changes over the last five to ten years.  To fully appreciate the changes which have occurred in this field, one must first step back and look at the rationale of performing such a transplant.  To begin, patients with malignant disease usually undergo some form of standard therapy such as surgical removal of the tumor, chemotherapy to destroy the cancerous cells, or radiation to destroy tumor masses.  Fortunately many patients are cured of their disease.  However in some patients the disease is not entirely cured by standard therapy.  When malignancies such as leukemia recur after chemotherapy, scientists have discovered that these cancer cells have developed resistance mechanisms.  One of the best understood mechanisms of chemotherapy resistance is the formation of a pump on the surface of the cancer cell which when activated is able to effectively pump chemotherapy back out of the cell so that the cancer cell is not poisoned and hence not killed.  Fortunately, researchers have realized that if the dose of chemotherapy is increased by a factor of two to twenty times that of standard doses, then so much chemotherapy is able to get inside the cells and hence overwhelm the pumps so that the cancer cells can be destroyed.  Unfortunately, giving such high doses of chemotherapy may result in irreversible damage to the bone marrow.  Regrettably one can not live without a functioning bone marrow because it is a “factory” which produces three major types of blood cells that are essential for life:  white blood cells that fight infection, red blood cells that carry oxygen from the lungs to the vital organs of the body, and platelets which are small particles which prevent us from bleeding.  Hence, if one were to destroy the bone marrow completely, then the consequences would be death secondary to either infection or bleeding.  Luckily, scientists have discovered cells inside the bone marrow called stem cells which are essentially “seed” cells which are capable of growing back new bone marrow within approximately 10 – 20 days.  Transplant physicians are thus able to harvest the stem cells from the bone marrow and then freeze them in liquid nitrogen.  After the stem cells are safely frozen, a patient can then be given high dose myeloablative (i.e. marrow destroying) chemotherapy and/or radiation therapy designed to eradicate the cancer cells.  After the chemotherapy has washed out of the patient’s body, the stem cells are then defrosted and subsequently infused into the blood stream where they will travel throughout the body and eventually return to the bone marrow; after approximately 10 to 14 days the marrow will begin to function again and produce normal WBC’s, RBC’s, and platelets.  Hence, the stem cell transplant is considered a rescue technique after high dose chemotherapy. 

In the past, the stem cells were harvested from the bone marrow directly; however, we are now able to collect the stem cells from the blood stream from patients after they have been given a growth factor which causes the stem cells to move from the marrow into the circulation. The instrument used to harvest the stem cells is called an apheresis machine.

 The type of transplant described above is called an autologous transplant as the stem cells are actually collected from the patient before the high dose therapy is given.  The other major form of transplant is referred to an allogeneic transplant where the stem cells are collected from a donor (usually a brother or sister).  An allogeneic transplant has an added benefit as the patient is essentially getting a brand new immune system.  Scientists have now recognized that it is this new immune system which is often able to eradicate tumor cells which still remain despite patients receiving high dose therapy.  This phenomenon is known as graft versus tumor (GVT) effect.  Another interesting phenomena was noted when patients who had relapsed after an allogeneic transplant, subsequently   were able to be placed back into a complete remission and ultimately cured of their disease when immune effector cells (T-lymphocytes) from the donor were reinfused into the patient. This information lead to a paradigm shift in the transplant field and hence lead to the birth of the non-myeloablative allogeneic stem cell transplant which is also known by other names such as: “mini-allo” transplant, “transplant lite”, “drive-thru” transplant, “reduced intensity” transplant, or “mixed chimera” transplant.  One might ask why then can’t the donor stem cells be infused directly into a patient without the need for giving chemotherapy.  Unfortunately if this is done the patient’s immune system is strong enough to reject the donor cells and thus destroy them.  However if a patient is given low doses of immunosuppressive chemotherapy and/or low doses of total body irradiation (TBI), the patient’s immune system can be suppressed enough so as to allow the donor immune cells to slowly grow in the patient’s body.  The state is called a mixed chimeric state which essentially means that the patient’s blood contains cells of the donor and the patient.  During this time, the patient is maintained on low doses of immunosuppressive drugs such as Cyclosporine for several weeks.; the donor immune system grows and gradually overtakes the patient’s immune system. As this takeover occurs the donor immune system also destroys the cancer which is remaining in the patient’s body.  Over a period of several weeks to several months, many patients will achieve a complete remission and ultimately be cured of their cancer.

“Mini-allo” transplants have numerous advantages.  Because lower doses of chemotherapy are given, the transplant is much less toxic and in some studies 60% of patients undergoing this form of therapy did not require any hospitalization and those requiring hospitalization were in the hospital for an average of 8 days compared to the normal 28 to 42 day length-of-stay for a standard allogeneic transplant.  In addition, this form of transplant can be applied to older patients up to the age of 70; previously standard allogeneic transplants can only be given to patients up to the age of approximately 55.  Another added advantage of this form of transplant is that it is likely to be less expensive because of the decreased hospital stay and lower complication rate. 

In 1997 only a handful of these “mini-allo” transplants have been performed, but in the year 2000, over one thousand have been performed worldwide.  Diseases in which this form of transplant are likely to be effective include:  chronic myeloid leukemia, chronic lymphocytic leukemia, mantle cell lymphoma, and low-grade non-Hodgkin's lymphoma.   There are also studies that suggest patients with acute myeloid leukemia, intermediate grade lymphoma, multiple myeloma, and Hodgkin’s disease may also benefit.  At this point in time, most institutions reserve the “mini-allo” transplants for older patients or for those who have other health problems which make them ineligible for a standard stem cell transplant.  However, this is rapidly changing and such non-myeloablative transplants are being tested in a wider patient population.