Stem cell transplantation involves the transfer of lympho-hemopoietic stem cells. This transfer can take place back into the patient him/herself (autologous), or into a different human being (allogeneic). Until about 15 years ago, such stem cell transplants (SCT) nearly always utilized bone marrow, but more recently the use of "mobilized" stem cells from the peripheral blood has become increasingly popular.

Indications for SCT
There are basically three major indications for SCT. The most frequent indication is the attempt to overcome the side effects of very high-dose chemotherapy. Such transplants, which may be autologous or allogeneic, are performed for breast cancer and other solid tumors, malignant lymphoma, myeloma, and acute leukemia in remission.
     The second indication is to replace defective stem cells; the defect may be acquired (e.g., aplastic anemia), or congenital (e.g., immunodeficiencies, sickle cell anemia, or certain metabolic disorders). Obviously, only allogeneic SCT can fulfill this role.
     The third indication for SCT is to utilize the immune system of the donor to fight a malignancy in the recipient. Again, only allogeneic SCT can exert this "adoptive immunotherapy" (1), which is often called a "graft vs. tumor" effect.

Preparative Regimen
Typically, the infusion of stem cells is preceded by a preparative regimen of chemotherapy with or without total body irradiation (TBI).This preparative regimen has the effect of killing tumor cells, creating "space" in the marrow cavity for the new stem cells to engraft, and paralyzing the immune system of the recipient, in order to decrease the risk of rejection of allogeneic stem cells.
     Autologous SCT for malignant lymphoma probably relies only upon the first effect of the preparative regimen, whereas for allogeneic SCT for chronic muelogenous leukemia (CML) all three effects are of essence. During allogeneic SCT the various effects of the preparative regimen occur simultaneously, and for many years the importance of each single effect was not addressed.
     The high risk of relapse of CML after syngeneic twin SCT or after allogeneic SCT with T-cell depleted stem cells suggests that the tumoricidal effect of the preparative regimens used (mainly TBI + Cytoxan, or Busulfan + Cytoxan) was insufficient to completely eliminate the malignant clone, and that the infusion of immunocompetent cells (e.g., T-cells) with the stem cells is pivotal for the curative effect of allogeneic SCT. Thus, to cure CML the "graft vs. leukemia" effect appears more important than the preparative regimen.

Complications
All SCT preparative regimens consisting of high-dose chemotherapy and / or radiation have the potential for extensive toxicity. Mucositis, diarrhea, and transient pancytopenia are inevitable side-effects of most preparative regimens, and these complications are synergistic in dramatically increasing the risk of bacterial and fungal infections.
     Loss of appetite and energy, alopecia, and nausea / vomiting are very frequent and add to poor physical and emotional tolerance of the transplant procedure. Any decrease in toxicity, without concomitant loss of efficacy, would be desirable.

Misleading name
This combination of factors led to the introduction of "mini-transplant" or "transplant-lite," both of which are unfortunate misnomers. These allogeneic transplants use less toxic preparative regimens but still have all the risks of any stem cell transfer between two immunologically nonidentical individuals, i.e., rejection, graft-versus-host disease, and immunodeficiency with increased risk of (viral) infection.
     The main goal of a "mini-transplant" is to establish the allogeneic stem cell graft in the recipient with as little toxicity as possible. Since the myelotoxic effect of the preparative regimen is far less, most of the antitumor effect of the allograft will have to come from the "graft vs. tumor" effect - the immunological attack of the tumor by the donor's transferred immune system.

Factors in chemotherapy
The amount of chemotheraphy / radiation necessary to allow allogeneic engraftment depends on a large number of factors, among which allosensitization, dose of stem cells, HLA-match, post-transplant immunosuppression, and available marrow "space" are the most important. A number of different preparative regimens have in common that they do not permanently eradicate bone marrow function of the recipient, although many of these regimens do cause transient marrow aplasia. Such regimens are lumped together under the name "non-myeloablative" preparative regimens.
     The MD Anderson group used a combination of fludarabine (120 mg/m²) with either idarubicin (36 mg/m²) and Ara-C (8 g/m²) or melphalan (140 mg/m²), or a combination of 2-CDA (60 mg/m²) and Ara-C (5 g/m²)(2). Infusion of

Other studies
Slavin et al., in Jerusalem used fludarabine (180 mg/m²), oral busulfan (8 mg/kg), and antilymphocyte globulin as the preparative regimen for stem cell transplant from HLA-identical siblings in 26 patients with a variety of hematologic diseases (5). Some patients did not develop transient severe neutropenia, and 4 patients did not require any platelet transfusions. All patients had full or partial engraftment with donor cells.
     At the NIH, Barrett et al., used fludarabine 125 mg/m² incombination with cyclophosphamide (120 mg/kg) to prepare 11 patients for stem cell transplants from HLA-identical siblings; all patients had at least partial engraftment with donor cells (6).
     Sykes et al., were able to establish engraftment of HLA-mismatched donor stem cells in four out of five patients with lymphoma, following a preparative regiment of cyclophosphamide 200 mg/kg, thymic irradiation, and antilymphocyte globulin before and after the infusion of stem cells. The patients showed mixed chimerism, with lymphoid cells mostly of donor origin, but myeloid lineages to a varying degree still of recipient origin (7).
     Whereas all these studies used a combination of a purine-analog with a myelotoxic drug, the Seattle group used a single dose of 200 cGy total body irradiation as their preparative regimen (8). This dose of 200 cGy does not appear to cuse irreversible bone marrow failure, at least in dogs. In combination with cyclosporine (Neoral®; Sandimmune®), and mycophenolate mofetil (CellCept®) as immunosuppressive agents, allogeneic engraftment can be obtained in humans, as was predicted from the dog model.
     At a recent meeting, Storb presented data on 56 patients with hematological malignancies (9). The patients had a median age of 56 years, and had a nadir of their white cells of around 750 / mm³ occurring between 15 and 20 days after stem cell infusion. Engraftment was documented in about 80 percent of cases and mostly represented mixed chimerism.

New discoveries
These studies indicate that the old adage that required intense immunosuppression of the recipient prior to transplant, to allow engraftment of allografts, particularly of mismatched allografts, no longer holds.
     With more powerfull immonosupporessive agents after transplant, and with higher doses of donor stem cells (often mobilized peripheral blood stem cellsP, engraftment may now be established in situations that were unthinkable even a decade ago.
     Two different concepts have led to the use of "non-myeloablative" preparative regimens for allografts. The first, and currently most frequently applied, aims to establish donor stem cell engraftment with the minimal amount of toxicity from the preparative regimen. This concept relies completely upon the "graft vs. tumor" effect of the allograft to fight the underlying malignancy in the recipient.
     For many patients the "cost" of lack of tumoricidal effect of the preparative regimen is more than offset by the benefit of lower organ damage. In particular, patients with less than optimal organifunction due to treatment, concomitant disease, or age may benefit from such an approach.

Establishing full chimerism
Patients at the high end of the age spectrum where allografts may be considered (50 to 70 years) have been most frequently included in the studies reported. This concept aims for full chimerism, with all hematologic cells ultimately of donor origin.
     If mixed chimerism is found, withdrawal of immunosuppression and / or infusion of donor lymphocytes (DLI) are used to make the chimerism complete. Consequently, for many patients the secondary aim is to establish full chimerism gradually. At this point, the lymphokines released by recipient cells as a result of the preparative regiment will have subsided. The absence of high levels of lymphokines, in combination with the temporary persistence of recipient myeloid cells, may lead to less aggressive graft vs. host disease (GvHD).

Permanent, mixed chimerism
The second concept that may be pursued with non-myeloablative allografts is the establishment of permanent and stable mixed chimerism. This therapy would be curative for many genetic diseases, such as

Changing beliefs
Use of terms such as "mini-transplants" or "transplant-lite" have led many observers to believe that such allografts are easier or less complicated. In fact, some insurance companies do not even count allografts following a nonmyeloablative preparative regimen among the allograft experience of transplant centers.
     Physicians with limited or no experience in allgrafting embark on mini-transplants under the assumption that these transplant procedures are less challenging than allotransplants using a more intense preparative regimen.
     Frankly, nothing could be farther from the truth. Non-myeloablative regiment allografts exchange early toxicity for the risk of delayed complications. The situation is not unlike that of T-cell depletion of allografts.
     During the years that T-cell depletion of allografts was very popular, the early toxicity of the transplants clearly decreased. Effective prevention of severe GvHD necessitated less use of steroids, and resulted in fewer infections and less organ toxicity.
     Unfortunately, the incidences of graft rejection and disease recurrence increased. Currently, few transplant centers still use T-cell depletion for average-risk allografts.
     Non-myeloablative regimens cause less organ toxicity, but the use of highly immunosuppressive drugs (fludarabine, mycophenolate mofetil, antilymphocyte globulin) appear to increase the risk of viral and fungal infections (10,11). Furthermore, rejection of donor stem cells seems to be more frequent.

GvHD debate
As far as GvHD is concerned, the jury is still out. Some studies suggest that GvHD is less of a problem than after allografts with "regular" preparative regimens, but most studies report considerable GvHD.
     The decrease in immediate toxicity of the preparative regimen, in combination with the very short duration of pancytopenia after the use of mobilized peripheral blood stem cells, allow non-myeloablative allografts to take place at least partly in the outpatient setting. This fits the trend of providing an increasing part of stem cell transplant care outside the hospital, in order to increase patient comfort and decrease cost.
     In addition, non-myeloablative allografts follow the current trend to "tailor" the transplant after the need of the individual patient. An allograft can be established without excessive toxicity, and the decision whether full or partial chimerism is optimal for this individual patient can be delayed until after toxicity has subsided, one may hope for a lower complication rate, and improved overall, and disease-free, survival rates. Allografts following non-myeloablative regiments are a logical development in transplant biology, just as purification of stem cells and the use of HLA-mismatched donors.
     IBMT introduced in 1999 a protocol for allografting following a preparative regimen of fludarabine (125 mg/m2) and cyclosphosphamide (4,200 mg/m2). Peripheral blood stem cells, mobilized from HLA-identical siblings with the help of G-CSF, are used at a dose of at least 3 x 106 CD34+ cells/kg. Cyclosporine is used after transplant to modulate GvHD.
     If at day +30 mixed chimerism is detected by VNTR technique, the cyclosporine is rapidly tapered to try to induce full chimerism. If leukemic cells persist, donor lymphocyte infusions may be considered to enhance graft vs. Leukemia effect. So far, four patients (median ag 50 years) have been transplanted with this regimen. Non myeloid toxicity was minimal, and two patients did the entire transplant as an outpatient. Between the four patients, only a total of two platelet transfusions were necessary, and the absolute granulocyte count exceeded 500 / mm3 between 13 and 15 days after stem cell infusion.
     A patient with CML failed to engraft and showed autologous recovery of Ph+ cells. a patient with AML is in complete remission and a full chimera at 11 months after transplant; mild chronic GvHD is present. Two patients had therapy resistant chronic lymphocytic leukemia. One is in complete remission and a full chimera about six months after transplant; the other still is a mixed chimera and has a decreasing population of leukemic recipient cells (around 20 percent) in the bone marrow. All have a Karnofski score of 90 to 100 percent.

Conclusion
In summary, "mini-transplants" are a promising new tool in the armamentarium of stem cell transplant. The misleading name has led some physicians and payrs to conclude that "mini-transplants" represent a "diluted" form of allotransplant that is more easily performed and has fewer possible complications. This is certainly not the case.
     Until much more is known about the effect and side effects of non-myelablative preparative regimens preceding allografting, such transplants should only be performed by physicians experienced in the care of allograft recipients and donors using investigational protocols.