The history of acute promyelocytic leukaemia

Why should the British Journal of Haematology devote an article to the history of acute promyelocytic leukaemia (APL)? Because APL is probably the best example of a disease where the dialogue between physicians and scientists has provided a chance to make several advances in both clinical practice and basic sciences. Most patients with APL are now cured. Oncogenesis and the reversion of oncogenic events are now better understood. APL was the malignant disease to be treated by cell modulation, using agents which act specifically on oncogenic events. The recent history of APL could, in fact, be subdivided into three periods: before, during and after treatment with all-trans retinoic acid (ATRA). During the first period (1957–1988), the disease was defined; during the second (1988–1993), a specific treatment, later recognized as targeting the oncogenic event, dramatically improved the prognosis of the disease and, during the third post-ATRA period (1991–2002), the main achievements were improved knowledge of cellular and molecular biology, including the control of protein expression and degradation, and a new discovery: the beneficial effect of arsenic. Acute promyelocytic leukaemia (APL) was first described in 1957 by the Swedish author Leif Hillestad (Fig 1). He reported three patients characterized by ‘a very rapid fatal course of only a few weeks’ duration, a white blood cell picture dominated by promyelocytes, and a severe bleeding tendency due to fibrinolysis and thrombocytopenia′. He noted ‘a normal ESR (erythrocyte sedimentation rate), probably caused by the reduced fibrinogen concentration in the plasma’. His conclusion was that the disease ‘seems to be the most malignant form of acute leukaemia’. One of the three patients had previously been described by Stormorken (1956). The first description of APL by Leif K. Hillestad. From: Hillestad, L.K. (1957) Acute promyelocytic leukaemia. Acta Medica Scandinavica, 159, 189–194; copyright Blackwell Publishing Ltd. Leif Hillestad also mentioned that previously, Cooperberg and Neiman (1955) had described a patient with acute myelogenous leukaemia with fibrinolytic purpura, which was ‘identical to his cases’ and that a similar patient had also been described by Pisciotta and Schultz (1955). Leif Hillestad also thought that a patient reported by Risak (1935), with a ‘rapid down hill course and the coincident rise of myelocytes in the peripheral blood’, might have been APL. Leif Hillestad concluded the introduction to his 1957 report by the statement that: ‘a logical name of this type of leukaemia is acute promyelocytic leukaemia’. In the first series of 20 patients recorded during the pre-ATRA period, Bernard et al (1959) described more detailed features of the disease. At the sixth European Congress of Haematology in 1957, Jacques Caen (Caen et al, 1957) reported the occurrence, in haematological malignancies, of a fibrinolytic syndrome which he defined more precisely 2 years later as acquired fibrinopenia (Caen et al, 1959). In fact, the most impressive clinical feature of APL at diagnosis was the occurrence of severe bleeding diathesis. Patients with APL experienced muco-haemorrhages combined with purpura and abundant ecchymotic subcutaneous haemorrhages. A significant proportion of patients (20–30%) died rapidly of cerebral haemorrhage. The disease constituted an individual entity, mainly because of its more hyperacute outcome compared with other forms of acute leukaemia; the two clinical features defining APL were the characteristic morphology of malignant cells and the presence of severe fibrinopenia. Larger numbers of typically promyelocytic malignant cells were found in the bone marrow than in the blood. The peripheral blood white cell count was low, and blasts had a monocytoid appearance. The predominant malignant cells in bone marrow were described as resembling abnormal promyelocytes, with an immature nucleus and a copious cytoplasm filled with several azurophilic granules. An abundance of large granules sometimes covered and masked the nucleus. Auer rods were found in many cells, grouped into what were called faggots. In 1976, the well-characterized morphology of these malignant cells led the French–American–British (FAB) Nomenclature Committee to assign them the specific classification of M3 cells (Bennett J.M. et al, 1976). Four years later, a rare variant form of APL, the hypogranular variant, was officially recognized by this Committee. It was characterized by cell nuclei that were usually bilobed, with no granules visible on light microscopy and a positive myeloperoxidase reaction (Bennett et al, 1980). Patients with this variant form experienced similar coagulation disorders, but often had a high white blood cell (WBC) count. A third, very rare variant form, basophilic microgranular APL, was described in 1982 (McKenna et al, 1982). Thus, APL and its morphological variants were identified within a 15-year timespan. Nevertheless, the clinical management of the disease remained a nightmare for physicians as a result of the unpredictable onset of life-threatening bleeding disorders. Bernard et al (1973) reported that the disease was particularly sensitive to treatment by anthracyclines, which resulted in a high rate of complete remission. However, chemotherapy exacerbated the bleeding diathesis, thus increasing the risk of early death. Two major disorders, thrombocytopenia and fibrinogenopenia, were considered responsible for the coagulopathy. Although everybody agreed on the presence of fibrinogenopenia and high levels of serum fibrinogen–fibrin degradation products, the origins of the fibrinogenopenia gave rise to several controversial discussions, which led to the adoption of different therapeutic approaches: was it due to disseminated intravascular coagulopathy (DIC) with secondary fibrinolysis, to primary fibrinolysis, or both? Apart from platelet transfusion, what was the best treatment: low-dose heparin, antifibrinolytic drugs, or no treatment at all? DIC was most frequently incriminated, because of the presence of D-dimers and the decreased levels of factors V and X. Low-dose heparin was usually included in treatment protocols. However, in contrast to the usual features of DIC, normal survival time of platelet and fibrinogen levels had been shown in APL patients (Bennett M. et al, 1976). Avvisati et al (1988) further reported normal levels of protein C and antithrombin III. The noted an acquired of concluded that the fibrinolytic than DIC, was the main responsible for the diathesis. In the the of fibrinogenopenia and the best of the bleeding were Apart from the description of the two major clinical the morphology of malignant cells and the coagulation disorders, APL had been as a by the presence of an abnormal was at first considered by et al as a of However, a later, the identified it as a between the of and et al, and APL was with this by et al APL patients have the because of an or In the APL defined by three the presence of the M3 cell morphological of the the occurrence of fibrinogenopenia and the presence of the specific and on the management of APL treatment and on the to a fatal of the during the first of treatment et al, The beneficial effect of the treatment by Bernard et al (1973) was in and the factors of APL were rapidly identified by Bernard et al as the of the fibrinogenopenia and the high count. The was also by using high or an of factors included and serum or to complete was only due to to which was reduced by treatment et al, a later by the et al, but also to fatal haemorrhages. The as to the fibrinogenopenia and were due to DIC or primary fibrinolysis as as the between The only positive therapeutic was the for platelet during patient two that using and result in than et al, et al, the of this period, APL was both and and was treated with and platelet The complete rate was the early rate and the rate At 2 the rate after complete was Thus, of patients for more than 2 years and were considered because are rare in this type of acute leukaemia. In the new that agents a in cells, thus the of the of malignant the cell of blood cell in he had the first in which normal blood cells from be and the of the that the and of also that cells from cell after and be to normal and to or as a result of by et al, of cells different in this et al, also that cells from were into in normal after et al, 1982). In the of the cell by et al (1988) the of agents that were of than agents were of retinoic into into and anthracyclines, into One of the best for the treatment of several of leukaemia was low-dose to the in of two cell and using a concentration of et al, et al, patients treated with low-dose et al, a complete remission. 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Thus, of the of coagulopathy and bleeding usually during patients experienced a rapid no primary to the no and few were The most feature was the of malignant cells in the bone sometimes combined with the presence of Auer rods in et al, In to with because of the An events. from no but several patients were with this of a of to make the but its to to the of the in At that was for the treatment of cell leukaemia. the of in the a controversial in on the or effect of the to to a of was in with was by the of as he thought that the of a complete by in of malignant cells was and to that his of treatment be at the in the which series of bone marrow from several APL patients at after treatment, the was by this new treatment, and to make the a result of at only for the treatment of APL but also for an clinical of the of the clinical for in and by as as the cellular were in et al, et al, in with an in the which the is APL treated by A similar to treated by a malignant cell malignant its is (Fig The that had in had been in after the with all-trans retinoic acute promyelocytic leukaemia a leukaemia or a was in From: Acute promyelocytic of with The of treatment for APL, and the of the retinoic acid by et al (1988) on the of at a to the at which had the and to further the and provided by et al, of the in and by and of the at the in an of in cells from APL a found in normal or in patients with other of leukaemia. also noted in as shown by and concluded in APL, the in an article these was to a but was on the that the were due to and at The a in the no in APL. 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The survival rate was and the rate was In during the of the of Haematology at in to which and were two from reported that of had been with similar positive in of The first which had in included patients and in of and and experienced complete The second included patients of complete and three were to treatment, as as and of complete and to to of the of Haematology in (Fig to patients in after and and reported that of them complete remission. The only had the in malignant cells at et al, In fact, is an that was in the to leukaemia (Fig It is that the few patients with a outcome at that time were APL of the first by the of of for in that best treatment for leukaemia is the of from the of Haematology and cellular of malignant cells at and at et al, have acquired with this and found that it was for the in patients et al, The clinical effect of was first by et al at the and by several in and improved the bleeding in APL and only the primary fibrinolysis but also the DIC, thus the and of APL cells et al, the now as the is a for and as a with The has two main the and of In the of the to called of retinoic acid and and which are to to of the et al, the on thus the In an between and to thus the The also the retinoic acid protein which is the first of et al, was to be a of al, An et al, by as as the by et al, a to the of the molecular in APL. et al that: the protein a with and as a with a of the from the were in to the et al, a new in the treatment of as other of leukaemia as the with had a similar a that also included APL is a for the of the between expression and The of expression other than the of is mainly due to of of treatment be using as of or Thus, the was that a of the on which the between and of of the of and the forms of acute which were APL but a in which of the of the was features of were similar to APL. The first of these was identified in APL by et al and the was called The disease was to as a result of a second to with a to et al, He et al, However, in the by noted for the disease was sensitive to the of and et al, a cells also other as of the for the or several et al, In both treatment by was and a prognosis similar to APL. However, in of the patients usually had a high count. In by and that the targeting of and the of and that this was by the degradation of these et al, of the et al, The two drugs, and are to normal to the malignant two on of the first an of on and and and the and the oncogenic in In the both are to the The of this to with The first were because were and had no in was due to the of by no is The of only to but also to The second of was to the APL disease. were using of in Two gave positive using et al, and the other using expression et al, that leukaemia after a to a that APL and was sensitive to and arsenic. several using only the but also the and other of which is a He concluded that is oncogenic in et al, are in his with of and using and et al using an APL by cells from APL et al, only that or had a beneficial effect on APL more that the of and the disease. The died haematological or molecular of APL. The effect of the and on patients is In is to to patients as a treatment, because two of patients treated in experienced severe et al, is as a in treatment or for patients in and is or combined with in several including the and but it is as a several are on the in to new the in the of a for APL, by or the disease et al, APL has been defined as most malignant form of acute the forms of acute leukaemia 1957) and is now in at of APL is the first of a malignant disease to be treated by on an oncogenic that the of the cell as in are APL is the main form of leukaemia in which are treated by with two drugs, and on the and in the protein The knowledge of the of of these to that treatment be to forms of leukaemia other than APL, mainly by the of as and of between and of APL that acute are due to which APL is also a for the of molecular of disease is now recognized as a after the treatment of APL is a for treated by that oncogenic it and a of new treatment was in patients with a in malignant cells and in patients with were in leukaemia patients treated with et al, A second due to the presence of a of the of the in on are during treatment and to a is also found in patients with leukaemia during treatment with several are now to in the that several are in the treatment of The history of APL has to an and several have been in basic and clinical the of APL, is to that several forms of acute leukaemia be by specifically