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Medical Progress

Indian Pediatrics 2000;37: 397-406

Acute Lymphoblastic Leukemia: Current Treatment Concepts

L.S. Arya

From the Division of Pediatric Oncology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi 110 029, India.
Reprint requests: Dr. L.S. Arya, Professor, Division of Pediatric Oncology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi 110 029, India. Fax: 91-11-6862663.

Acute lymphoblastic leukemia (ALL) has served as a model for cancer research in children as well as adults. Because of the major advances in diagnosis, development of rational use of combination chemotherapy, specific central nervous system (CNS) preventive therapy and improved supportive care, the cure rate in childhood ALL has increased tremendously and at present approximately 70-80% of children with ALL are potentially cured(1,2). This manuscript provides an overview of current concepts in classification, prognosis and treatment of ALL.

 Epidemiology

Acute lymphoblastic leukemia (ALL) is the single most common pediatric malignancy accounting for one fourths of all childhood cancer and three fourths of all newly diagnosed leukemias(3). The incidence of childhood ALL is approximately 3-4 cases per 100,000 children under the age of 15 years(3,4). Overall, males experience a slightly higher leukemia risk than females. This male preponderance is particularly evident in adolescent boys with T-cell ALL. There is a significant peak in childhood ALL incidence that occurs between the ages of 3 and 5 years. This peak is mainly due to pre B-ALL cases (referred to as "common ALL") in this age range.

The etiology of ALL remains unknown in a vast majority of cases. However, there are several genetic syndromes that have been associated with an increased risk of childhood leukemia(5). In particular, there is a 10-20 fold increased risk of leukemia [both ALL and acute myeloid leukemia (AML)] in children with Down syndrome. Other genetic syndromes associated with childhood leukemia include Bloom syndrome, Fanconi’s anemia, Neuro-fibromatosis, Klinefelter’s syndrome, Immuno-deficiency and Ataxia telangiectasia. Studies on environmental factors have focussed on expo-sure both in utero and postnatally. Ionizing radiation and certain toxic chemicals can pre-dispose to development of leukemia. Thera-peutic irradiation has been associated with a higher risk of acute leukemia. In recent years particular attention has been paid to the development of secondary AML after aggres-sive chemotherapy, particularly, alkylating agents and epipodophyllotoxins(2).

 Cellular Classification

Morphology: ALL cells can be classified using the French-American-British (FAB) criteria(6). The FAB system divides ALL into three morphologic subtypes (L1, L2 and L3). L1 lymphoblasts, the most common in children (80-85%) have scanty cytoplasm and inconspicuous nucleoli. In most studies, L1 morphology is associated with a better prognosis. Blasts in the L2 category account for 15% of cases, are large and more pleomorphic in size, and have more abundant cytoplasm and prominent nucleoli. Only 1-2% ALL cells demonstrate L3 morphology in which cells are large, have deep cytoplasmic basophilia, with prominent cyto-plasmic vacuolation and are morphologically identical to Burkitt’s lymphoma cells. L3 morphology is associated with surface immunoglobulin and should be treated as Burkitt’s lymphoma.

Immunophenotype: A panel of monoclonal antibodies is needed to establish and to distinguish the immunologic subclasses of leukemia. Most groups now classify the ALL into B-cell precursor, a B-cell or a T-cell leukemia. Precursor B-cell ALL is further subdivided into early pre-B and pre-B. B-cell precursor include CD19, CD20, CD22 and CD79. Mature B-cells are characterized by immunoglobulins on their surface, while the T-cell ALL carry the immunophenotypes CD3, CD7, CD5 or CD2. The specific myeloid markers include CD13, CD14 and CD33. Very rarely the leukemic cells may express both myeloid and lymphoid antigens, the leukemia is considered to be biphenotypic. On the basis of these immunophenotypic analysis a firm diagnosis can be made in 99% of cases.

Cytogenetics: Technological improvements now make it possible to demonstrate abnor-malities in chromosmal number and/or structure in the majority of cases of ALL(2,7). The presence of hyperdiploidy (chromosome number >50) is associated with a very good prognosis in contrast to the dramatic poor prognosis in patients with hypodiploid (chormosome number <45 per cell)(8-10). Specific chromosomal translocations in ALL include the classical t(8;14) in B-cell ALL, t(4;11) in infant leukemia and t(9;22) trans-location (that forms the Philadelphia chromo-some) are associated with a poor prognosis(11-13). The recognition of these abnormalities have contributed a lot to our understanding of the pathogenesis and prognosis of ALL patients(14,15).

 Prognostic Factors and Risk Assessment

Thirty five years ago almost all children with acute lymphoblastic leukemia were dying with their disease and consequently all were considered as high risk. However, after intro-duction of chemotherapy and now, advances in cell biology and molecular genetics, the risk factors have been defined. It was clear from clinical experience that childhood ALL could be divided into many prognostically distinct subtypes. The concept of risk adopted therapy was introduced in the late 1970’s by Riehm and his group(16). Different study groups have defined different risk groups on the basis of clinical and biological features present at the time of diagnosis such as age at diagnosis, WBC count, sex, tumor load, CNS disease at diagnosis, immunophenotype, cytogenetics and DNA content and response to therapy. The two most important prognostic factors are age at diagnosis and the initial WBC count. This is confirmed in almost all studies and can be the basic factors for choosing treatment strategies in ALL patients. Children less than one year of age have a very poor prognosis. Infant leukemia is often associated with a genetic abnormality t(4;11) translocation and has high WBC count. Children between the age of 1 and 9 years do very well. WBC count more than 50,000/mm3 at diagnosis has a bad prognosis. The Immunophenotype has prognostic value. The prognosis in B-cell leukemia (L3 morphology) which had a very bad prognosis earlier, has improved considerably with specific B-cell (Burkitt’s) leukemia directed protocols(17,18). T-cell ALL was also considered a high risk leukemia but recent results with intensive therapy have shown that T-cell leukemia per se is not a bad prognostic factor unless it is associated with other high risk factors like high WBC count, mediastinal mass or CNS disease at diagnosis(19). The prognostic value of gender is controversial. Some studies report no difference in prognosis between boys and girls(5) but other centers especially from UK(19,20) and nordic countries(21) have found a significantly higher relapse rate in boys. Cytogenetic abnormalities in leukemic cells have a definite prognostic value(22). Hyper-diploidy (>50 chromosomes) has a very good prognosis while hypodiploidy (<45 chromo-somes) has a worse prognosis. Philadelphia positive t(9;22) ALL and translocation t(4;11) which is present in infant leukemia are associated with a very poor prognosis. Several groups particularly the BFM(23) have adopted response to single agent prednisolone as an in vivo prognostic factor. According to this study a blast cell count of ³1000/mm3 peripheral blood after a 7 day exposure to prednisolone and one intrathecal dose of methotrexate identified 10% of the patients as having a significantly worse prognosis. In another study the presence of blasts in the bone marrow on day 7 or 14 was associated with a severe prognosis(24). Participants at a recent workshop sponsored by National Cancer Institute(25) agreed that in B-cell precursor ALL, an age between 1 and 9 years and a WBC count less than 50,000/mm3 should be the minimal criteria for lower risk ALL and all other patients should be classified as high risk.

 Treatment

Since the introduction of "total therapy" as first described by Pinkel in 1971(26), the prognosis in ALL has improved from <5% survival before 1965 to 25-50% during the 70’s to 70% during 80’s and 80% for children diagnosed in the 1990’s(2,27). The main reason behind this spectacular survival in ALL is more effective global multidrug regimens in well-defined clinical trials(18,23,28-33). The successful treatment of ALL requires the control of bone marrow or systemic disease, as well as the treatment (or prevention) of extramedullary disease in sanctuary sites, particularly in the central nervous systems (CNS). The cornerstone of this strategy is systematically administered combination chemotherapy together with CNS prophylaxis.

The treatment of ALL is divided into 4 stages: (i) Induction (to attain remission) therapy, (ii) Intensification (consolidation), (iii) CNS prophylaxis or CNS preventive therapy, and (iv) Maintenance or continuation therapy. Intensification (consolidation) of therapy following remission induction may not be used in low risk patients, however recent studies indicate that early and/or delayed intensification therapy improves the long term survival in both low risk as well as high risk ALL patients(16,20,23). The average duration of treatment in ALL ranges between 2 and 2½ years and there is no advantage of treatment exceeding 3 years(34,35). The two drugs regimen of vincristine and prednisolone induces remission in 80-90% of children with ALL. Since both the remission rate and duration of remission can be improved by the addition of a third or fourth drug (L-asparaginase and/or anthracycline) to vincristine and prednisolone, current induction regimens include vincristine, prednisolone, L-asparaginase with or without anthracycline and a remission rate is achieved in 95-98% of cases(18,22). The remission induction therapy lasts for 4 to 6 weeks.

 CNS Directed Therapy

The concept of CNS preventive therapy is based on the fact that most children with leukemia have subclinical CNS involvement at the time of diagnosis and central nervous system acts as a sanctuary site where leukemic cells are protected from systemic chemotherapy because of the blood brain barrier. The early institution of CNS prophylaxis is essential to eradicate leukemic cells which have passed the blood brain barrier. CNS prophylaxis has made a major contribution to the increased survival rates in leukemia. Most children receive a combination of intrathecal methotrexate and cranial irradiation. Recent attention has been focussed on the long term neurotoxicity and rarely development of brain tumor with this combination. The current goal is therefore to achieve effective CNS prophylaxis while minimizing neurotoxicity. Most studies now show that a lower dose of cranial irradiation (1800 cGy) with intrathecal methotrexate is as effective as 2400 cGy cranial irradiation with intrathecal methotrexate and is used in most CNS preventive therapy regimens(36,37). Other alternative regimens used for CNS prophylaxis include the use of triple intrathecal therapy consisting of methotrexate, hydrocortisone and cytarabine(38,39) without cranial irradiation. Many investigators avoid cranial irradiation and now administer intensive intrathecal and/or systemic chemotherapy which includes high dose methotrexate (5 g/m2 as a 24 hour infusion)(40). High dose methotrexate is not used in view of the difficulty of measuring methotrexate levels and the greater difficulty in administering methotrexate at high doses in India. Currently in the west cranial irradiation is used in patients who have very high risk features at diagnosis like T-cell ALL with WBC count >100,000/mm3, Philadelphia chromo-some positive ALL and presence of CNS leukemia at diagnosis(1,41).

 Intensification (Consolidation) Therapy

This is a period of intensified treatment administered shortly after remission induction. Somenew chemotherapeutic agents are adminis-tered to eradicate residual blast cells and tackle the problem of drug resistance. There is enough evidence to suggest that intensification of treatment has improved the long term survival in all patients and it has become a common practice in many treatment protocols particularly for high-risk patients(5,20,23,28,42). The most commonly used drugs for intensification or consolidation therapy include high dose methotrexate, L-asparaginase, epipodo-phyllotoxin, cyclophosphamide and cytarabine (Ara-C)(1,2,20,23). There is no doubt that the upfront intensification of treatment particularly in poor risk patients with ALL has been the main reason for the improvement in survival. The more intensive therapy, however, has resulted in prolonged periods of granulo-cytopenia which has led to the greatly increased importance of supportive care, including the liberal use of broad spectrum antibiotics and blood products.

 Maintenance (Continuing) Therapy

Once remission has been achieved, therapy is continued for an additional 2-2.5 years. Without maintenance or continuation therapy all patients except B-cell ALL which can be treated with short term (<6 months) high-dose chemotherapy as used in pediatric non-Hodgkin’s lymphoma(17,43), relapse within 2-4 months. It has been estimated that approximately two to three logs of leukemic blasts are killed during the induction therapy, leaving a leukemic cell burden in the range of 109-1010. Therefore, additional therapy is nece-ssary to prevent relapse. A large number of drug combination and schedules are used for maintenance, some based on periodic reinduc-tion, others on continued delivery of effective drugs. The main drugs used for maintenance therapy include 6-mercaptopurine daily and methotrexate once a week given orally with or without pulses of vincristine and prednisolone or other cytostatic drugs. Monthly pulses of vincristine and prednisolone appear to be beneficial(44). In high-risk ALL most investi-gators use more aggressive treatment and use additional drugs during maintenance therapy(23,28,42). It is imperative to carefully monitor children on maintenance therapy for both drug related toxicity and compliance. For better outcome both the drugs methotrexate and 6-mercaptopurine should be given to the limits of tolerance as determined by absolute neutrophil counts(45,46).

 Supportive Care

Because of the potential complications encountered with treatment and the need for aggressive supportive care like blood component therapy (red blood cell and platelet transfusion), detection and management of infectious complications, nutritional and metabolic needs and psychosocial support these children should be treated by a specialist in pediatric oncology in a cancer center or hospital with all the necessary pediatric supportive care facilities including pediatric nursing care, good diagnostic and laboratory support in hemato-logy, microbiology radiology, clinical chemistry and blood banking(47). Several studies have shown that survival rates of children with leukemia or any cancer are significantly enhanced through access to state-of-the-art treatment given according to well defined protocols in specialised centers, compared to pediatric cancer patients not enrolled on protocols and treated in other hospitals(48-50).

 Treatment After Relapse

Despite the success of modern treatment, 25-30% of children with ALL still relapse. Therefore, the main cause of treatment failure is relpase of the disease. The most common site of relapse is in the bone marrow (20%), followed by CNS (5%) and testis (3%). The prognosis for a child with ALL who relapses depends on the site and time of relapse. Children with late relapse have a better prognosis than those with early relapse(51,52). Early bone marrow relapse before completing maintenance therapy have the worst prognosis and long time survival of only 10-20% while late relapses occurring after cessation of maintenance therapy have a better prognosis (30-40%). Relapse in extramedullary sites particularly testes compared with bone marrow relapse is more favorable in terms of survival(52). The treatment of relapse must be more aggressive than the first line therapy with induction of new drugs to overcome the problem of drug resistance. Several studies have suggested that allogeneic bone marrow transplantation offers the better chance of cure than conventional chemotherapy for children with ALL who enter a second remission after hematologic relapse(52-56). In addition to the treatment related morbidity and mortality, one of the main problems of allogeneic transplantation is the nonavailability of a suitable matched donor. As an alternative to matched marrow transplants from related donors some investigators have tried the role of autologous transplantation which offered no substantial advantage over chemotherapy(57,58). The facility for bone marrow transplantation is available in major centers in India including Mumbai, Vellore, Chennai and Delhi. The overall survival after relapse is 20-40% in different series.

 Late Effects of Treatment

Long term effects of treatment which may take years to become apparent are of increasing concern. Therefore, continued evaluation of a child with ALL survivor for prolonged periods is an essential part of follow-up. It is now clear that children who received cranial irradiation at a younger age are at increased risk of cognitive and intellectual impairement and development of CNS neoplasms(59,60). There is a risk of development of secondary acute myeloid leu-kemia after the intensive use of epipodophylo-toxin (etoposide or tenoposide) therapy(61,62). Endocrine dysfunctions leading to short stature, obesity, precocious puberty, osteoporosis, thyroid dysfunction and growth retardation due to growth hormone deficiency are reported(5,63-65). The most worrying late effect of treatment is anthracycline induced cardiac toxicity(66-68).

 Survival of ALL in India

There are very few published reports on the long term survival of childhood ALL from India. There is an ongoing Indo-US multicentric trial for characterization and treatment of ALL at Cancer Institute, Madras; Tata Memorial Hospital, Mumbai; All India Institute of Medical Sciences, New Delhi; and Kidwai Memorial Institute of Oncology, Bangalore. The five year survial of patients of ALL from these centers is reported to be 45% to 55%(69,70). The event free survial from our center is about 51%(71). Various reasons have been attributed to the decreased survival of cancer in children as a whole and ALL in particular in our country in comparison to the west(72,73). One of the most important reasons is the financial burden of treatment resulting in poor compliance and large number of dropouts. The high incidence of infections among the immunocompromised cancer patients, lack of availability of good supportive care and poor tolerance to chemotherapy by malnourished patients also contribute to increased mortality. There is a considerable evidence of adverse biological and genetic factors in play. It has been noted that T-cell leukemia and cytogenetic abnormalities that predict poor outcome are more common in Indian children with ALL(74-76). Over the years there has been a significant improvement in the outcome of ALL patients in our country and the future is encouraging.

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