Treatment of Childhood Acute Lymphoblastic Leukaemia

Treatment Overview

Treatment of children with acute lymphoblastic leukaemia (ALL) has many potential complications and requires aggressive supportive care (transfusions, management of infectious complications, and emotional, financial, and developmental support). Consequently, this treatment is best coordinated by paediatric oncologists and performed in cancer centres or hospitals with the necessary paediatric supportive care facilities. It is equally important, however, that clinical centres and specialists directing the patient's care maintain contact with the referring physician in the community.

Successful treatment requires the control of systemic disease (marrow, liver and spleen, lymph nodes) as well as the treatment (or prevention) of extramedullary disease, particularly in the central nervous system (CNS). Although only 3% of patients have detectable CNS involvement by accepted criteria at diagnosis, unless specific therapy is directed toward the CNS (intrathecal medication, cranial irradiation, high-dose systemic chemotherapy with metho-trexate or cytarabine), 50 to 70% of children will eventually develop overt CNS leukaemia. Therefore, all children with ALL should receive systemic combination chemotherapy together with some form of CNS prophylaxis.

Children with ALL are usually treated according to risk groups defined by both clinical and laboratory features. A subset of the known prognostic factors (eg, age, white blood cell [WBC] count at diagnosis, presence of specific cytogenetic abnormalities) are used for initial stratification. Risk-based treatment assignment allows those children who would be expected to have a good outcome with modest therapy to be spared more intensive and toxic treatment, while a more aggressive (and thus more toxic) therapeutic approach can be provided for patients who have a lower probability of long-term survival.¹

Treatment is divided into stages: remission induction, consolidation or intensification, and maintenance (continuation) therapy, with CNS sanctuary therapy generally provided at each stage. An intensification phase of therapy following remission induction is used for all patients. The intensity of both induction therapy and postinduction therapy is determined by the clinical and biological prognostic factors utilised for risk-based treatment assignment. The average duration of maintenance therapy ranges from 2 to 3 years.

Untreated Childhood Acute Lymphoblastic Leukaemia

Induction Chemotherapy
Most centres treat patients at standard or lower risk of treatment failure with a 3-drug induction therapy regimen (prednisone/dexamethasone, vincristine, and L-asparaginase) in conjunction with intrathecal therapy. For patients at high risk for treatment failure, a more intense induction regimen (4 or 5 agents) may result in improved event-free survival,^2-4 and high-risk patients generally receive induction therapy that includes an anthracycline in addition to vincristine, prednisone/dexamethasone, plus L-asparaginase.

In general, patients will achieve a complete remission within the first 4 weeks. Patients who require more than 4 weeks to achieve remission have a poor prognosis. Outcome is also less favourable for patients who demonstrate more than 25% blasts in the bone marrow or persistent blasts in the peripheral blood after 1 week of intensive induction therapy. Protocols of the Children's Cancer Group base treatment decisions on the day 7 bone marrow response for high-risk protocols or day 14 bone marrow response for standard-risk protocols.⁵

Central Nervous System Sanctuary Therapy

A current goal of ALL therapy design is to achieve effective CNS sanctuary therapy while minimising neurotoxicity. Every patient with ALL receives intrathecal chemotherapy with methotrexate plus cytarabine and hydrocortisone. Intrathecal chemotherapy may be the sole form of presymptomatic CNS therapy or it may be combined with systemic moderate- to high-dose infusion of methotrexate with leucovorin rescue and/or cranial radiation (1200 to 1800 cGy). High-risk patients with rapid early response to therapy appear to have adequate CNS prophylaxis with intrathecal therapy alone.⁶ Children who present with CNS disease at diagnosis (defined as 5 white cells/mm³ in cerebrospinal fluid [CSF] with lymphoblasts present) generally receive cranial radiation, with or without concurrent spinal radiation, in addition to appropriate systemic and intrathecal chemotherapy. Toxic effects of CNS-directed therapy for childhood ALL are listed in Table 1.

Table 1. Toxic effects of CNS-directed therapy.

Childhood Acute Lymphoblastic Leukaemia in Remission

Consolidation/Intensification
Once remission has been achieved, systemic treatment in conjunction with CNS sanctuary therapy follows. The intensity of the postinduction chemotherapy varies considerably, but all patients receive some form of 'intensification' following achievement of remission and before beginning continuous maintenance therapy. Intensification may involve the use of intermediate- or high-dose methotrexate, the use of similar drugs to those used to achieve remission, the use of different drug combinations with little known cross-resistance to the induction therapy drug combination, the extended use of high-dose L-asparaginase, or combinations of the above.

For children with standard-risk disease, regimens utilising a limited number of courses of intermediate- or high-dose methotrexate have been used with good results. Another treatment approach for decreasing late effects of therapy utilises anthracyclines and alkylating agents, but limits their cumulative dose to an amount not associated with substantial long-term toxicity. An example of this approach is the use of 'delayed intensification', in which patients receive an anthracycline-based 'reinduction' regimen and a cyclophosphamide-containing 'reconsolidation' regimen at approximately 3 months after remission is achieved. The use of 'delayed intensification' improves outcomes for children with standard-risk ALL, in comparison to that achieved without an intensification phase.

For high-risk patients, a number of different approaches have been used with comparable efficacy. These treatment approaches employ multi-agent regimens that are not restricted to antimetabolites, since antimetabolite-based therapy has been shown to be inadequate for patients with high-risk ALL. Treatment for high-risk patients generally includes blocks of intensified therapy, such as the 'delayed intensification' blocks (reinduction/reconsolidation) used by the Children's Cancer Group and by the German Berlin-Frankfurt-Munster (BFM) group. For high-risk patients with slow early response to therapy, augmented BFM therapy has been shown to improve outcome. The augmented BFM regimen utilises 2 courses of 'delayed intensification', while also intensifying therapy with repeated courses of intravenous methotrexate (without leucovorin rescue) given with vincristine and asparaginase.

Maintenance Therapy
The backbone of maintenance therapy in most protocols includes daily oral mercaptopurine and weekly oral methotrexate. If the patient has not had cranial irradiation, intrathecal chemotherapy for CNS sanctuary therapy is generally given during maintenance therapy. Clinical trials generally call for giving oral mercaptopurine in the evening there is evidence that this practice may improve event-free survival.⁷ It is imperative to carefully monitor children receiving maintenance therapy for both drug-related toxicity and for compliance with the oral chemotherapy agents used during maintenance therapy. It is also important for physicians to recognise that some patients may develop severe haematopoietic toxicity when receiving conventional dosages of mercaptopurine because of an inherited deficiency of thiopurine S-methyltransferase, an enzyme that inactivates mercaptopurine.⁸ These patients are able to tolerate mercaptopurine only if dosages much lower than those conventionally used are administered.

Pulses of vincristine and prednisone/dexamethasone are often added to the standard maintenance regimen. Dexamethasone is preferred over prednisone for younger patients with ALL (children aged 1 to 9 years). Extending the duration of maintenance therapy to 5 years does not appear to improve outcome.⁹

Bone Marrow Transplant for Philadelphia Chromosome-positive Acute Lymphoblastic Leukaemia

Bone marrow transplant (BMT) using an HLA-matched sibling as a donor appears to improve disease-free survival for patients with Philadelphia chromosome-positive ALL. The outcome of BMT using an unrelated or partially matched donor may be inferior to chemotherapy.¹⁰

Recurrent Childhood Acute Lymphoblastic Leukaemia

The selection of therapy for the child whose disease recurs during or shortly after therapy depends on many factors including prior treatment, whether the recurrence is medullary or extramedullary, and individual patient considerations (Table 2). Aggressive approaches, including bone marrow transplantation, should be strongly considered for patients with marrow relapse occurring during treatment or within 6 months of termination of therapy, or late marrow relapse with high tumour load as indicated by a peripheral blast count of 10,000/µL or more.¹¹ For patients with an early marrow relapse, allogeneic transplant from an HLA identical sibling or matched unrelated donor that is performed in second remission has resulted in longer leukaemia-free survival when compared with a chemotherapy approach.

Table 2. Prognosis associated with recurrent childhood acute lymphoblastic leukaemia.

Site/time of relapse Prognosis for long-term survival Bone marrow   During initial therapy/ within 6 months of discontinuation chemotherapy 10-20% following salvage 1 year after discontinuation of initial therapy chemotherapy 30-40% following salvage T-cell <20% following salvage chemotherapy Isolated extramedullary relapse   Isolated CNS relapse >18 months after initial therapy 4-year EFS in 80% with aggressive systemic and intrathecal therapy plus craniospinal irradiation Isolated testicular relapse   During initial therapy 3-year EFS of 40% Late relapse 3-year EFS of 85%

Abbreviation: EFS = event-free survival.

References

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2. Tubergen DG, Gilchrist GS, O'Brien RT, et al. Improved outcome with delayed intensification for children with acute lymphoblastic leukemia and intermediate presenting features: a Childrens Cancer Group phase III trial. J Clin Oncol 1993;11: 527-537.

3. Gaynon PS, Steinherz PG, Bleyer WA, et al. Improved therapy for children with acute lymphoblastic leukemia and unfavorable presenting features: a follow-up report of the Childrens Cancer Group Study CCG-106. J Clin Oncol 1993;11:2234-2242.

4. Schorin MA, Blattner S, Gelber RD, et al. Treatment of childhood acute lymphoblastic leukemia: results of Dana-Farber Cancer Institute/Children's Hospital Acute Lymphoblastic Leukemia Consortium protocol 85-01. J Clin Oncol 1994;12:740-747.

5. Nachman JB, Sather HN, Sensel MG, et al. Augmented post-induction therapy for children with high-risk acute lymphoblastic leukemia and a slow response to initial therapy. N Engl J Med 1998;338:1663-1671.

6. Nachman J, Sather HN, Cherlow JM, et al. Response of children with high-risk acute lymphoblastic leukemia treated with and without cranial irradiation: a report from the Children's Cancer Group. J Clin Oncol 1998;16:920-930.

7. Schmieglow K, Glomstein A, Kristinsson J, et al. Impact of morning versus evening schedule for oral methotrexate and 6-mercaptopurine on relapse risk for children with acute lymphoblastic leukemia. J Pediatr Hematol Oncol 1997;19:102-109.

8. Relling MV, Hancock ML, Rivera GK, et al. Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyl-transferase gene locus. J Natl Cancer Inst 1999;91:2001-2008.

9. Richards S, Gray R, Peto R, et al. Duration and intensity of maintenance chemotherapy in acute lymphoblastic leukaemia: overview of 42 trials involving 12 000 randomised children. Childhood ALL Collaborative Group. Lancet 1996;347:1783-1788.

10. Arico M, Valsecchi MG, Camitta B, et al. Outcome of treatment in children with Philadelphia chromosome-positive acute lymphoblastic leukemia. N Engl J Med 2000;342:998-1006.

11. Buhrer C, Hartmann R, Fengler R, et al. Peripheral blast counts at diagnosis of late isolated bone marrow relapse of childhood acute lymphoblastic leukemia predict response to salvage chemotherapy and outcome. J Clin Oncol 1996;14:2812-2817.