Acute Promyelocytic Leukaemia in Children
Acute promyelocytic leukaemia is characterized by coagulopathy, distinctive haematological findings and diagnostic (15;17) translocation. We reviewed all our patients with acute promyelocytic leukaemia managed between 1983-94. Diagnosis was based on blood and marrow findings according to French-American-British classification. There were 8 patients (5 males, 3 females), accounting for 44.4% of children with acute myeloid leukaemia seen in the same period. Bleeding diathesis was common on presentation. Coagulopathy was evident in four patients. Three patients failed to achieve remission after induction. Two of the three died of disease progression while one went into complete remission after allogeneic marrow transplant but died of bronchiolitis obliterans 1 year later. Five patients achieved complete remission. Four of the five (80%) relapsed within the first year (one died, one defaulted, one currently being reinduced, one survived for more than 2 years after marrow transplant from a matched unrelated donor). The overall survival was 37.5%. All-trans retinoic acid was given to three patients, all resulted in remissions without adverse reactions.
Keyword : Acute promyelocytic leukaemia; All-trans retinoic acid; Bone marrow transplantation; Chemotherapy; Incidence
Acute promyelocytic leukaemia (APL) is a subgroup of acute myeloid leukaemia with distinct clinical and haematological features.1,2 APL is designated as M3 by the French-American-British (FAB) classification. The disease is characterised by coagulopathy, peculiar promyelocytes (Faggot cell, Fig.) in bone marrow, and association with specific cytogenetic feature of (15:17) translocation.
In adults, this entity accounts for up to 15% of all acute myeloid leukaemia (AML) cases. Scanty information is available on APL in children. The incidence of paediatric APL is generally quoted to be less than 10% of all paediatric AML cases (Table I).3-7 In this study, we reviewed our patients with APL with special reference to the incidence, clinical features and haematological findings on presentation, and treatment outcome, especially on the use of all-trans retinoic acid (ATRA).
Patients and Methods
Patients presented with a diagnosis of APL to our unit between 1983 and 1994 were reviewed in retrospect. The diagnosis of APL was confirmed by reviewing the blood and marrow specimens taken at the time of presentation according to the French-Amercian-British (FAB) classification. Cytogenetic analysis results, if available, were noted. The case records were reviewed in detail.
Eight patients with APL were identified. Seven were newly diagnosed patients seen at our unit and one (Case 8) was treated in another hospital and referred to us for marrow transplant because of induction failure. Their age ranged from 3.3 years to 12.7 years (median 8.3 years). The total number of paediatric patients with AML during the same period was 18 (11 males and 7 females) with median age approximately one and a half year younger than that of the APL patients. Thus APL made up of 44.4% of our total AML patients.
Their clinical features were shown in Tables II and III. One of the two patients who had menorrhagia presented with hypovolaemic shock. Anaemia was present in 4 (50%) patients. Thrombocytopenia was present in 6 (75%), all of whom had platelet count less than 50 x 109/L. The presenting white cell count ranged from 2.2-43.2 x 109/L. The proportion of abnormal promyelocytes in peripheral blood ranged from 4-80%. Promyelocytes constituted over 80% of nucleated cell population in the marrow. Coagulopathy was evident in 4 (50%) with prolongation of thrombin time in one and low fibrinogen level in three. Prothrombin time and activated partial thromboplastin time were not significantly abnormal. Cytogenetic study was available in our three recently diagnosed patients (case number 4,5 and 8). All of them exhibited the unique (15; 17) translocation.
Seven patients received chemotherapy alone for induction. The remaining one received a course of all-trans retinoic acid (ATRA) before chemotherapy. The chemotherapeutic agents used were the standard regimen at the time of diagnosis. In general the major components were cytarabine and anthracycline. We treated the three recently diagnosed patients with the UKAML X protocol.
After the induction phase, five of our patients (including the one with ATRA given) entered first complete remission (CR1), while the remaining three did not. For the five patients with CR1, 4 relapsed during treatment, all within the first year. One of them died about a month after the relapse. One was diagnosed to have CNS relapse, but he defaulted, for his parents refused cranial irradiation. The third entered second remission with ATRA, and subsequently received bone marrow transplant from a matched unrelated donor (MUD). The fourth was the one given ATRA prior to chemotherapy. She relapsed 11 months after the end of induction and she is now under re-induction at the time of this report. The one remaining in CR1 has been followed-up disease-free for more than 5 years (Table III). For the three patients who could not achieve CR1, two died as a result of disease progression. The terminal events included uncontrolled sepsis and profound coagulopathy. The remaining one entered remission with ATRA and then received marrow transplant from an HLA-matched younger brother.
For the two patients who underwent BMT, the one with a MUD transplant after relapse, is now more than 2 years disease-free. The second one, who received an allogeneic marrow from her younger brother, suffered from chronic graft versus host disease and died of respiratory failure as a result of bronchiolitis obliterans. She was free from leukaemia at the time of death. The overall survival was 37.5%. The survivors have been followed up for 68, 39, 16 months respectively for Case 1, 4, 5.
Our experience in the use of ATRA was limited to 3 patients (case no. 4,5 and 8). One received ATRA early prior to chemotherapy. One was given ATRA after failed induction by chemotherapy, and the third one after relapse. The dosage used was 45 mg/m2/d. Duration of treatment lasted from 2 to 4 weeks. All the three patients achieved haematological remission at the end of treatment. Severe symptoms of toxicity were absent.
In contrast to adult patients, there is relatively scanty information on paediatric APL. The proportion of APL within AML obtained from large-scale studies were low, not exceeding 10% (Table I).3-7 Small-scale studies tend to give unusually high rates.8,9 The incidence rates by some large scale Italian studies were also high.5,10 Owing to our small sample size, we cannot conclude at this stage that APL is an unusually common form of AML in our population.
Virtually all our patients were found to have coagulopathy at some stages of their disease course. The mechanisms of coagulopathy in APL have been comprehensively reviewed.11,12 Fibrinolytic processes have been shown recently to be an important mechanism responsible for bleeding diathesis. This provides rationale for the use of antifibrinolytic agents such as epsilonaminocaproic acid and tranexamic acid in the control of bleeding diatheses associated with APL.
The experience in the use of ATRA in the treatment of adult APL has accumulated substantially in recent years.1,2,13-15 ATRA, with its differentiating action, appears to be the best inducer of complete remission in APL at diagnosis and in relapse.2 However, the remission achieved by ATRA was short-lived. One paper reported the longest duration of complete remission in patients treated exclusively with ATRA has been 16 months.16 As a consequence, patients achieving CR with ATRA still require chemotherapy.17-19 Such a combination has been proved to reduce relapse and improve survival in adults.20,21 The information of ATRA therapy in paediatric patients is scarce. The toxicity with its use are many and some are severe e.g. hyperleucocytosis, respiratory distress but the frequency in the paediatric population is unclear. Although our experience in ATRA therapy is limited, it appears to be safe and effective to achieve remission in paediatric APL patients.
In summary, APL represents a special subtype of leukaemia with characteristic clinical and haematological features. The use of differentiating agent ATRA should be considered as the standard for initiaitng treatment for APL, even in paediatric patients. We had a fairly high rate of induction failure and relapse in those who could achieve CR1. Bone marrow transplant is indicated in these circumstances. In our experience, BMT could be used to achieve remission of the disease but the morbidity and mortality associated with the procedure can be significant.
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