CK Li, MK Shing, KW Chik, DH Lai, TK Lam, MP Yuen

Abstract

Patients diagnosed to have acute myeloid leukaemia in Prince of Wales Hospital were retrospectively analyzed. From 1984 to 1995, a total of 36 newly diagnosed cases were included in the study. The mean age of diagnosis was 6.5 years. Acute myelomonocytic and megakaryocytic leukaemias were the commonest subtypes. Hyperleucocytosis occurred in 28.2% of patients. Fifteen patients were treated with less intensive treatment in the earlier years (Group A). Twenty patients were treated with a more intensive treatment in the more recent years (Group B). Group A patients had lower remission rate as compared with Group B (66.6% Vs 84.2%). Early deaths and non-leukaemia deaths during remission occurred in ten patients (27.6%). Five patients received bone marrow transplantation two unrelated allogeneic and three autologous BMT. The 5 years disease free survival of Group A and Group B patients were 32.0 % and 57.2% respectively. Intensive chemotherapy improved the cure rate in acute myeloid leukaemia patients.

Introduction

Leukaemia is the commonest form of childhood malignancy. In 1982-1991, 40% of the childhood malignancies in Hong Kong are due to leukaemia. Acute lymphoblastic leukaemia (ALL) is the commonest type of childhood leukaemia. Acute myeloid leukaemia (AML) constituted 18.4% of childhood leukaemia during the same period. The treatment result of AML was much worse than that of ALL. The 5 year event-free survival of AML treated by chemotherapy was in the range of about 20-30%.¹ A previous review of our local experience showed similar result.² In recent years new approaches were attempted to improve the unsatisfactory results. These included the use of allogeneic and autologous bone marrow transplant (BMT), and very intensive induction and consolidation treatment in short duration. The early results of these treatment modalities are encouraging. This paper is a retrospective review of the treatment result of AML in a single institution over the past twelve years.

Patient and Method

From 1985 to July 1995, all the AML cases diagnosed and treated in Prince of Wales Hospital, Hong Kong were analyzed retrospectively. AML cases referred from other hospitals for treatment of relapsed AML or BMT were excluded. AML cases developed from underlying myelodysplastic syndromes were also excluded. The patient characteristics at diagnosis were analyzed. The subtypes of AML were classified according to the French - British - American (FAB) classification. Remission of leukaemia was defined as bone marrow with regenerating normal haemopoietic cells and contains less than 5% blast cells. Relapse of leukaemia was defined as more than 5% blast cells in the bone marrow after achievement of remission. Central nervous system (CNS) leukaemia was defined as more than 5 x 10⁶/L identifiable blast in CSF. The treatment regimens were divided into two main groups. The patients diagnosed before 1989 were treated with various chemotherapy regimens. The induction protocols were quite heterogeneous which included daunorubicin or adriamycin and cytosine arabinoside with or without thioguanine. These patients were further treated with one or two courses of consolidation treatment, maintenance treatment was also given to some patients. All these protocols were considered as less intensive protocols according to present standard and were all grouped as one group (Group A). From 1989, majority of the patients were treated with a more intensive chemotherapy regimen which was modified from the United Kingdom MRC UKAML 10 protocol. Bone marrow transplant was included as part of the post-remission consolidation in the last few patients. These patients were grouped as Group B. The details of Group B treatment was shown in Table I. The patients were followed until their death or up to 1st December 1995. Patients received BMT after initial chemotherapy were also included in the analysis.

Result

Thirty-six patients with complete data were included in the analysis. The male to female ratio was 1:1, 18 males and 18 females. The mean age of diagnosis was 6.5 years, range from 0.2 to 14.4 years. There was no difference in the mean age for boys and girls, both being at 6.5 years. FAB M4 (Myelomonocytic leukaemia) was the commonest subtype of AML. Eight patients had FAB M7 (Megakaryocytic Leukaemia) subtype but 4 of them were having Down's syndrome. M2 (Myeloblastic with differentiation) and M3 (Promyelocytic Leukaemia) were the other more common subtypes. 54% of patients had their presenting white cell count (WCC) less than 20 x 10⁹/L. Hyperleucocytosis with WCC >100 x 10⁹/L occurred in 28.2% of the patients. The highest WCC was 444 x 10⁹/L. CNS leukaemia were diagnosed in 2 patients at time of diagnosis and both had very high WCC at presentation, 247 and 300 x 10⁹/L (Table II). There were 15 patients treated by the Group A regimen. A total of 20 patients were treated with regimen Group B. One patient died soon after diagnosis and did not receive any chemotherapy. Three patients received cranial radiotherapy as CNS prophylaxis whereas the other patients received intrathecal chemotherapy only.

There were five early deaths (13.8%) in the whole group of patients. These patients died within one month of diagnosis and their remission status could not be assessed. Two patients died of intracranial haemorrhage, two died as result of hyperleucocytosis and another died from typhlitis. Thirty-one patients could be analyzed for their remission status. Nineteen patients (61.2%) achieved remission after one course of induction chemotherapy. Three more patients achieved remission after second course of induction chemotherapy, thus 70.9% of the patients achieved complete remission after induction chemotherapy. In the Group A and B patients, complete remission rate after Course II chemotherapy was 66.6% and 84.2% respectively. Three of eight patients in Group A who achieved remission subsequently relapsed. Three of 18 patients in Group B who achieved remission also relapsed. Relapses occurred in bone marrow and there was no CNS relapse. All the relapses occurred within 18 months after remission. There was no late relapse after 18 months of continuous complete remission, five patients died from complications while still in first complete remission four due to infection, one due to metabolic complication.

Five patients were treated by BMT as consolidation treatment in first complete remission or for relapsed leukaemia. Three patients in Group B received autologous BMT while they were still in first complete remission and had completed the four induction consolidation courses. The autologous bone marrow was treated with mafosfamide ex vivo which was aimed at eradication of remaining leukaemia cells in the harvested bone marrow. Two patients received unrelated donor BMT, one for relapsed AML (Group A) and another for refractory AML (Group B). These patients were now still in remission after BMT with follow up of 1-20 months. All relapsed patients died within one year of relapse except one patient who received unrelated BMT and was already 20 months from BMT. Four patients in Group A (26.6%) were still surviving in first complete remission or second complete remission at a follow up period of 52-115 months. Twelve patients in Group B (60%) were surviving in first complete remission at a median follow up of 33 months (range 4-81 months). The 5 years disease free survival of Group A patient was 32.0%, and Group B patient was 57.2% (Fig).

Discussion

In the past few decades, there was much improvement in the treatment of childhood cancers. The overall long term survival of childhood cancers is now in the range of 60-70%. ALL, lymphoma and Wilms' tumour are the childhood malignancies with most remarkable improvement in the treatment results. AML is one of a common malignancy in children. The earlier results were unsatisfactory because of a low remission rate, high treatment related mortality and high relapse rate. Various cooperative trials had been designed to overcome these difficulties. The trend is now to use very intensive induction chemotherapy so as to improve the remission rate. However the recent result from Children Cancer Group in North America did not show such an improvement despite of very intensive induction.³ Our remission rate of Group B patients did show an improvement to 84.2% as compared to the earlier less intensive induction chemotherapy. The intensity of Group B induction treatment is comparable to other recent trials and the remission rate is also similar. It needs further improvement in the induction treatment so as to achieve a better remission rate. At the moment the remission rate in ALL is over 95%.

A high relapse rate is one of the main causes of treatment failure in AML. Maintenance treatment has been demonstrated to decrease the relapse rate and thus improve the long term disease free survival in ALL. However, maintenance treatment was not shown to be beneficial in AML patients.⁴ Our recent AML protocol also did not include a maintenance treatment phase. The current trend is to use very intensive post-remission consolidation treatment in short duration. The treatment is usually completed in six to nine months time. This approach did show a lower relapse rate in the recent trials.^5,6 This is associated with improvement in long term disease free survival, i.e. cure, to 40-50%. Unfortunately the very intensive treatment is usually associated with severe prolonged myelosuppression and immunosuppression. Treatment related deaths are more common in AML patients while in remission.⁷ In our series, there was a 13.8% of early death rate due to the high risk primary disease and complications. In addition, five patients (13.8%) died from complications during remission. The improvement in supportive treatment, such as more potent antibiotics and use of growth factors, may decrease these fatal complications.

The use of BMT in relapsed AML is the universally agreed treatment. Allogeneic BMT in the first remission (before relapse) had been accepted by most centres as the preferred option if a HLA identical family donor is available. The cure rate by allogeneic BMT is reported to be in the range of 50-60%. In some paediatric series the cure rate is even up to 80%.⁸ At the moment we are also adopting the same approach of transplanting AML patients in their first complete remission if HLA identical siblings are available. Unfortunately, only one third of patients might have HLA compatible family donors. Autologous BMT using the patients' own bone marrow for transplant while they are still in remission had been performed by many centres. However the advantage of autologous BMT is rather controversial.^5,7,9 The patients usually required a very long time for marrow recovery especially if the marrow had been treated ex vivo with pharmacological agents. Relapse rate after autologous BMT is also higher than that of allogeneic BMT. The most recent result of UK MRC AML 10 protocol did not demonstrate beneficial effect from autologous BMT as compared to chemotherapy only (Personal Communication, O.B. Eden). In the most recently opened trial, UK MRC AML 12 protocol, autologous BMT is not included as part of the treatment plan. Unrelated donor BMT is an alternative for patients who do not have HLA compatible siblings. However the complications after unrelated BMT are much higher and might even be fatal, e.g. graft versus host disease. Unrelated BMT is reserved for patients who had relapsed or refractory to treatment only.

Fig 3 years and 5 years disease free survival in Group A and Group B patients.

The 5 year disease free survival of our Group A patients was only 32.0%. This was similar to other studies using less intensive chemotherapy. The Group B patients did show a better early result, the 5 year disease free survival was 57.2%. There appeared to have an improvement in the survival rate but it did not reach statistical significance due to small number of patients. The role of BMT is more difficult to assess in this series because of small number of cases. The Hong Kong Paediatric Haematology & Oncology Study Group is now organizing cooperative trials among all the HA hospitals for various childhood cancers. With recruitment of more patients and longer follow up, we may thus be able to have a clearer picture on the treatment results. In conclusion, using more intensive chemotherapy protocol for treatment of AML appeared to improve the long term survival. The value of BMT in first complete remission, especially autologous BMT, needs further evaluation. Identification of risk factors in AML may help to define a group of patients who benefit most from this expensive and risky procedure.

Acknowledgment

Thanks Ms Stella Chan for her secretarial support. Thanks Children's Cancer Fund and The Hong Kong Paediatric Bone Marrow Transplant Fund for their generous support. Thanks all the nursing staff in Lady Pao Children's Cancer Centre for their expert care. Thanks Mr Kent Tsang for his technical support in bone marrow processing in BMT Laboratory.

References

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