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Abstract
Current intensive consolidation chemotherapy for patients with acute myeloid leukemia (AML) produces median remission duration of 12–18 months, with less than 30% of patients surviving 5 years free of disease. Post-remission therapy is necessary to prevent relapse in most patients with AML; therefore, the aim of post-remission treatment is to eradicate the minimal residual disease. Nevertheless, the optimal form of treatment is still under debate. The choice among the possible approaches (intensive chemotherapy, autologous or allogeneic hematopoietic stem cell transplantation) relies on two main factors: the expected risk of relapse, as determined by biological features, and expected morbidity and mortality associated with a specific option. In this review, we focus on the different preparative regimens before autologous and allogeneic hematopoietic stem cell transplantation in patients with AML, stressing the importance of an adequate conditioning regimen as a mandatory element of a successful AML therapy, in both the allogeneic and the autologous transplant setting.
Financial & competing interests disclosure
The authors were supported in part by AIL Pesaro Onlus. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.
No writing assistance was utilized in the production of this manuscript.
Key issues
Current intensive consolidation chemotherapy for patients with acute myeloid leukemia (AML) produces median remission duration of 12–18 months, with less than 30% of patients surviving 5 years free of disease. Post-remission therapy is necessary to prevent relapse in most patients with AML; therefore, the aim of post-remission treatment is to eradicate the minimal residual disease. Nevertheless, the optimal form of treatment is still under debate.
Clinical and laboratory observations show that most hematological malignancies exhibit a step dose–response reaction to alkylating agents and radiation therapy. Marrow toxicity is dose limiting for many of these agents. The goal of high-dose therapy regimens prior to autologous transplantation is to provide maximum therapy to eradicate malignant disease, limited only by non-hematological toxicity.
Total body irradiation (TBI) combined with cytoxan (Cy) emerged in the past as a standard. From the experience in a murine aplastic anemia model, Santos and Tutschka derived the potent myeloablative effect of busulfan (Bu) and translated this experience to humans. Bu/Cy slowly was accepted as a new standard conditioning regimen for myeloid leukemias and caused a shifting trend away from TBI in pre-transplant therapy for most myeloid disorders. This result was expected, considering the ease of administration and the lack of need for a TBI facility when using chemotherapy alone.
In more recent years, the issue of plasma levels of Bu emerged as one of the main topics of clinical trials in the transplant setting. Moreover, the use of Bu/Cy with pharmacokinetic-guided dose adjustment to achieve a steady state concentration plasma levels yielded longer disease-free survival S than did oral Bu/Cy without pharmacokinetic monitoring or with use of TBI/Cy.
The standard Bu/Cy scheme has been modified substituting mainly Cy, since it is considered as a not very active agent in AML, and its immunosuppressive effect is not necessary for autologous transplantation. Radiomimetic drugs other than Bu, or high-dose ‘leukemia-specific’ chemotherapy combinations, have been used to replace TBI: etoposide, cytosine arabinoside, nitrosourea and melphalan.
In the most recent years, with the development of the so-called reduce-intensity and reduced-toxicity conditioning regimens, the platform including Bu and fludarabine has been widely adopted. A relatively new and interesting drug included in the conditioning regimens for AML is treosulfan (Treo). Treo-based conditioning regimens can be considered as ‘low-toxicity’ combinations, with an anti-leukemic efficacy probably comparable to the one of the conventional myeloablative regimens. Treo is usually combined with fludarabine.
Both TBI- and chemotherapy-based conditioning regimens can be incorporated in a high-dose sequential treatment program for high-risk myelodysplasia syndrome or AML patients. This strategy is based on the use of a cytoreduction followed by the reduced-intensity conditioning administered early during the aplasia and has been widely adopted in the past years, challenging the conventional attitude to treat these patients with a standard induction regimen prior to allo-SCT. A very promising application of this strategy has been proposed by the German group with the fludarabine/amsacrine/cytosine arabinoside-sequential conditioning regimen.
The fact that hematological malignancies are relatively radiosensitive due, at least in part, to a limited ability to repair sub-lethal cell injury, has recently induced several investigators to focus on targeted radioimmunotherapy delivered at myeloablative doses as a component of preparative regimens prior to SCT to improve cure rates and reduce normal organ toxicities.
Although many efforts have been made in order to ‘pick the winner’ among the different conditioning regimens, no one has definitively overcome the others. In particular, even though the eradication of the leukemic stem cell is the goal of high-dose myeloablative regimens, increasing the dose of alkylators or TBI hasn’t improved the disease control. This may reflect the fact that the immune control of residual disease, mediated by graft-versus-tumor effect, may be even more important than the intensity of the conditioning. This latter observation is confirmed by the progressive expansion of the reduced toxicity and reduced intensity regimens.