HEMATOPOIETIC CYTOKINES IN THE BIOLOGY AND TREATMENT OF ACUTE MYELOID-LEUKEMIA - PERSPECTIVES AND CONTROVERSIES

In acute myeloid leukaemia (AML), age has a definite effect on the bio logy of the disease and also determines the outcome of chemotherapy. A ML cells constitutively express mRNA and produce several haematopoieti c cytokines. The haematopoietic cytokines: SCF, IL-3, GM-CSF and G-CSF induce leukaemic colonies or activate DNA synthesis in about 80% of A ML cases. Both M-CSF and thrombopoietin stimulated AML cell proliferat ion is seen in vitro in about 50% of cases. Both IL-6 and IL-11 showed little proliferative activity on primary AML cells. The combinations of these cytokines were synergistic in stimulating the proliferation o f AML cells. On the other hand, the inhibitory haematopoietic cytokine s: TNF-alpha, TGF-beta, IFN-gamma and IL-4 have shown multiple effects on AML blast cell proliferation. In several in vitro systems, haemato poietic cytokines have failed to induce maturation of AML blasts. Only in AML with t(8;21), G-CSF has induced granulocytic maturation of AML blasts in vitro. AML cells with chromosomal abnormalities involving t he 21q22 region differentiate in vitro into eosinophils in the presenc e of IL-5. IL-6 and IFN-alpha have induced megakaryocytic differentiat ion of blast cells from acute megakaryoblastic leukemia (M7) patients. The haematopoietic cytokines: SCF, IL-3 and GMCSF have protected in v itro AML cells from chemotherapy-induced apoptosis. Many clinical stud ies have been recently reported evaluating the effect of the haematopo ietic cytokines: GM-CSF, G-CSF, IL-3 and PIXY321 as adjuncts to the ch emotherapy of AML patients. Most studies have shown these haematopoiet ic cytokines to be well-tolerated and effective in augmenting neutroph il recovery in elderly AML patients when given after chemotherapy. On the other hand, considerable number of studies using these cytokines b efore and during chemotherapy to recruit AML cells into cell cycle and thus make them more susceptible to chemotherapy have reaveled no bene fit. Several clinical trials have shown promising results after the us e of IL-2 either as remission induction therapy in refractory and/or r elapsed AML patients or as post-remission consolidative immunotherapy. Haematopoietic cytokines administered after chemotherapy can shorten the duration of neutropenia and hospitalisation without a significant effect on treatment outcome. On the other hand, their use before and d uring chemotherapy has yielded no benefit, and instead have led to del ay of platelet recovery and worse survival rate in some elderly AML pa tients.