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General principles of treatment.

Treatment decisions depend not only on several factors, which may be summarized as follows: impact of disease, efficacy of the therapy and potential side-effects, but also on whether the disease has metastasized or not. As discussed in the previous chapters, hematological malignancies are generally systemic at diagnosis. It is more the exception than the rule that we are faced with local disease which may be treated with local therapies such as surgery or radiotherapy. Radiotherapy, however, has, historically, an important role especially in the treatment of Hodgkin’s disease. Since the introduction of this treatment modality, subsets of patients with Hodgkin’s disease could be cured. Currently, however, we are increasingly aware of potential long-term side-effects of our potent treatment options which results in new and adjusted recommendations especially in curable diseases where long-term side-effects have a significant impact. In the treatment of hematological malignancies, several treatment approaches can be discriminated as follows: induction, consolidation and maintenance therapy. Stem-cell transplantation (either autologous or allogeneic) is frequently applied. In addition, patients can be treated apart from chemotherapy with monoclonal antibodies (mAb) or radiotherapy. For several diseases wait-and-see policies are also applied. Induction chemotherapy is a part of an intensive treatment of acute leukemias. The aim is to bring patients in complete remission with one intensive cycle (sometimes two). If patients are in remission, the subsequent goal of the therapy is to prevent relapse. For this aim, consolidation therapy is used. Especially in acute lymphoblastic leukemia (ALL), many treatment protocols also contain maintenance chemotherapy. Generally, this is less immunosuppressive treatment given over a prolonged period of time. It is increasingly known that there is a significant dose– response relationship in the treatment of many hematological malignancies. One of the first significant side-effects, however, is related to bone marrow depression. To make high-dose therapy possible and to prevent long-term bone marrow depression, autologous stem cells can be reinfused after the high-dose therapy. This procedure is called autologous transplantation. Stem cells to be reinfused can be either harvested from the bone marrow or from peripheral blood after mobilization with chemotherapy plus growth factor support. An alternative approach is the transplantation using the stem cells of a donor [preferably human leukocyte antigen (HLA) identical]. The advantage of allogeneic transplantation is not only the use of noncontaminated stem cells but also especially the transplantation of the immune system of the donor which hopefully results in an immunological graft versus tumor effect (GvT). For this procedure to be effective, one needs effective immunosuppression which was in the past obtained by using the high-dose therapy as also used in autologous transplantation. Increasingly high-dose therapy is replaced by immune-suppressive treatment which enables the graft to grow and to exploit the GvT. Increasing knowledge has resulted in the discrimination of antigen (Ag) presence on tumor cells. The development of antibodies (Ab) that are directed against these Ags may have a significant antitumor effect. In hematology, the most important mAb is anti-CD20 which is very effective in the treatment of patients with all types of B-cell non-Hodgkin’s lymphoma (NHL). The working mechanisms are not completely elucidated but depend, among others, on complement activation and also antibody-dependent toxicity. Increasingly, mAbs are used in combination with standard chemotherapy, resulting in a higher efficacy. Historically, radiotherapy is a very effective option in the treatment of hematological malignancies. Relapses in irradiated areas are very rare. The major drawback of radiotherapy, however, is that it is only local therapy and, therefore, not effective against nonvisible areas of malignant diseases and, of course, in not irradiated areas. In the treatment of Hodgkin’s disease, it is now clear that the combination of radiotherapy with some cytotoxic regimens results in an increased likelihood of secondary malignancies which now has resulted in a more limited application of radiotherapy. In some hematological malignancies where the disease is relatively asymptomatic and cure cannot be achieved with current standard treatments, a wait-and-see policy (sometimes also called watchful waiting) can be applied. Diseases in which wait-and-see policies are applied include early stages of goodrisk chronic lymphocytic leukemia, asymptomatic stages of multiple myeloma and myelodysplastic syndromes (MDS) and asymptomatic patients with low-grade NHL.