Bone marrow transplantation risks

Hematopoietic stem cell transplantation and conditioning regimens

In the past referred to as bone marrow transplantation (BMT) but now termed hematopoietic (stem) cell transplantation (H(S)CT) because of the utilization of stem cell resources other than the bone marrow, HSCT constitutes a life-saving or life-prolonging intervention for many patients with hematologic malignancies and occasionally for patients with benign hematologic and non-hematologic disorders. The indications for HSCT have been rapidly evolving; innovations in HSCT, in combination with new targeted therapies for malignancies, allow older and more medically tenuous patients to be considered for transplantation. These developments have had a significant impact on pretransplant screening and posttransplant monitoring for cardiovascular diseases (CVD) in HSCT recipients.

Two types of HSCT can be distinguished: autologous and allogeneic. Autologous HSCT entails the use of the patient’s own stem cells for reconstitution of the bone marrow. These cells, which are collected in advance, allow for higher dose chemotherapy to be given, which is frequently employed for diseases such as recurrent non-Hodgkin lymphoma, Hodgkin lymphoma, and multiple myeloma. Allogeneic HSCT entails the use of stem cells from a donor to reconstitute the bone marrow. Early studies focused on the use of escalating doses of chemo- and radiation therapy to achieve the dual goals of more effective eradication of chemoresistant malignant cells and preventing immunologic graft rejection by paralyzing the recipient immune system. Chemotherapy doses can be escalated by about three-fold when healthy stem cells from a donor are used after chemotherapy exposure to repopulate the marrow. This strategy is effective because hematopoietic cells are much more sensitive to lethal toxicity compared with other organs, permitting escalation to a dose that is sublethal to other organs, especially the lungs, liver, kidneys, and heart. To permit such high doses of chemotherapy and radiation, patients who were considered appropriate candidates were highly selected to be young (typically <35 years) with excellent organ function.

Subsequent experience clearly indicated that high-dose chemoradiation was only partially responsible for eradication of malignant clone and that immunologic targeting by the donor’s immune system contributed significantly. In fact, this graft-versus-tumor effect was relatively more important in certain diseases, such as chronic lymphocytic leukemia, and relatively less so in other diseases, such as multiple myeloma (MM). It was also associated with potentially severe or life-threatening toxicity when the donor immune system targeted normal recipient tissues and organs resulting in graft-versus-host disease (GVHD) with potentially lethal injury to organs, such as the colon. This can result in bacterial translocation and sepsis, and in the context of immunologic dysregulation a high mortality rate.

Certain diseases that rely predominantly on chemotherapy dose escalation, such as dysproteinemic disorders and lymphomas, typically have much better outcomes when the recipient’s own stem cells are collected in advance of the high-dose conditioning regimen and reinfused afterward (autologous transplantation). This strategy works well when the stem cells are unaffected and the likelihood of transmitting malignant cells with the autologous stem cells is low. The toxicity of this approach is much lower because it avoids immunosuppressive drugs after the stem cell infusion and typically avoids the risk of GVHD. However, for other diseases, such as myeloid disorders, acute leukemias, and bone marrow failure syndromes, a donor-derived (allogeneic) graft is essential for disease control and bone marrow reconstitution, this approach is associated with much greater risk.

Increasing recognition that graft-versus-tumor activity could replace some of the benefit of high-dose chemoradiation for malignant cell eradication led to the possibility of less-intense chemotherapy regimens ( Table 5.1 and Fig. 5.1 ). Progress was accelerated with the development of the purine analogs (e.g., fludarabine and cladribine), which prevent graft rejection with less toxicity. These reduced-intensity or non-myeloablative regimens permitted older patients (into the 7th and 8th decade of life) and more fragile patients to be considered for allogeneic transplantation and thereby the advantage of potentially curative therapy. As a result, the comorbidity and risk spectrum for HCT has increased greatly in the current era.