DIFFERENTIATION OF MYELOID LEUKAEMIC CELLS: NEW POSSIBILITIES FOR THERAPY

The present status of therapy of acute myeloid leukaemia (AML) does not give much hope to chemotherapists and clinical haematologists (Gunz & Vincent, 1977). However, an interesting point was raised by Sachs (1978) in his recent annotation in this Journal. He suggested that a number of substances, including several cytotoxic drugs, could be exploited for their potential of inducing differentiation of myeloid leukaemic cells. One of these drugs is Arabinosyl Cytosine (ARA-C); its main action is on DNA replication (cell proliferation), and it can also affect the processes leading to cell maturation (Lotem & Sachs, 1974; Krystosek & Sachs, 1976). ARA-C is reputed to lead AML into complete remission through the killing of a substantial number of leukaemic cells. Such a cell killing effect of ARA-C a t the doses employed in AML is unquestionable, but the possibility also exists that ARA-C could also act by slowing down cell proliferation, so as to allow the cells that escape death to express their residual potential for differentiation and maturation. To test this possibility, we have scored the proportion of granulated versus non-granulated leukaemic blast cells before and immediately after a 24 h continuous infusion of ARA-C (total dose 10 mg/kg), in eight consecutive patients with AML, prior to any other therapy. The proportion of granulated blast cells became significantly higher after ARA-C in five of eight cases (mean value 31.6% before ARA-C, and 60.2% after the drug). In some patients the proportion of granulated cells before therapy was so low so as to make the diagnosis of AML difficult, but most of these 'undifferentiated' blast cells became clearly granulated after ARA-C. This was accompanied by a marked or total inhibition of cell proliferation, as shown by a drop of the mitotic index towards zero. The possibility that ARA-C can allow cell maturation through inhibition of cell proliferation is also suggested by the response to the drug of a patient with refractory anaemia with excess marrow myeloblasts. This is one of the haemopoietic dysplasias or preleukaemic disorders whose study may provide important information on human leukaemia (Dreyfus, 1976; Ricci et a l , 1978). This patient (Fig 1) was treated by red cell transfusions for 6 months. During that time he remained severely neutropenic (polymorphonuclears < 0.5 x 109/1) and thrombocytopenic (platelet count <50 x 109/l). At the sixth month he was given ARA-C in a very small dose (0.7 mg/kg/d i.v., for 7 consecutive days). 15-30 d after this course of ARA-C, platelet and polymorphonuclear (PMN) count became normal, and remained much higher than their pre-ARA-C levels for at least 6 months. During that time, the Hb level remained normal without any blood transfusion. Marrow was checked several times before and after ARA-C. Before ARA-C, the proportion of marrow myeloblasts ranged between 20% and 30%, and granulopoiesis was very defective, with very small numbers of myelocytes and PMN. Dyserythropoiesis was severe, and megakaryocytes were rare. After ARA-C, the proportion of marrow myeloblasts dropped to 5-lo%, with normal amount of myelocytes and PMN. Dyserythropoiesis became milder, and megakaryocytes were more frequent. Thus, the marrow picture remained abnormal, but cells matured better. Six months after ARA-C, the