High-risk ALL

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Information about High-risk ALL
Science-Technology

Published on January 12, 2009

Author: aSGuest10201

Source: authorstream.com

TREATMENT OF HIGH RISK ALL IN CHILDREN : TREATMENT OF HIGH RISK ALL IN CHILDREN Mohammad Jarrar, MD Associate Consultant Pediatric Hematology/Oncology INTRODUCTION : INTRODUCTION ALL is the most common malignancy in children , as it represents 23% of cancers diagnosed in children younger than 15 years, with an annual incidence of 31 per million. Peak age of presentation is between 2-3 years. With current treatments the 5 year overall survival for children with ALL ranges between 75-80%. CLASSIFICATION : CLASSIFICATION 80-85 % of cases of ALL in children are of B-precursor phenotype.Most of the remaining cases are of T-cell phenotype. A uniform risk classification by the NCI divides patients into 2 risk groups based on age and WBC at diagnosis.Those with WBC less than 50,000 and between the age of 1-9 years are classified as standard risk group. The remaining patients are high risk group. PRINCIPLES OF TREATMENT : PRINCIPLES OF TREATMENT A key to success in treating childhood ALL was risk tailored therapy. Current treatment protocols include the following phases: Induction, Consolidation, Interim maintenance, Delayed intensification(1 or 2) and a long maintenance phase. Length of treatment is 3 years for boys and 2 years for girls. INDUCTION : INDUCTION Four drug induction is generally used in high risk patients, which includes prednisone, L- asparaginase, vincristine and an anthracycline(usually daunomycin). Complete remission is achieved in over 95 % of the patients. CNS prophylaxis is provided by IT methotrexate (2 doses for CNS –ve and 4 doses for CNS +ve). INDUCTION : INDUCTION Controversial issues in induction: Prednisone versus dexamethasone: Although dexamethasone produces better CNS penetration and improved EFS in low risk patients(Bostrom et al, proceedings of ASCO 1998), it increases risk of aseptic necrosis in adolescents(Harris et al, Leukemia 2000) and was associated with increased septic deaths when used with anthracycline during induction(Hurwitz et al, Cancer 2000). INDUCTION : INDUCTION PEG asparaginase versus L- asparaginase: PEG form of asparaginase has a longer half life allowing less frequent administration and resulted in less antibody formation when used in standard risk patients(Avramis et al, Blood 2002). Day 7 bone marrow as a measure of initial response to therapy appears to be of significant prognostic value(Gaynon et all, Medical Pediatric Oncology 1990). CONSOLIDATION : CONSOLIDATION Current CCG/KFSH protocol based on standard BFM protocols uses Cyclophosphamide, 6- MP and ARA-C. Augmented BFM protocol adds vincristine and asparaginase to this phase. CNS prophylaxis is continued with 4 doses of IT MTX. INTERIM MAINTENANCE : INTERIM MAINTENANCE This stage is 2 months long and involves the use of oral anti-metabolites(6-MP and MTX)-standard BFM with the addition of vincristine and asparaginase in augmented BFM. Some protocols uses IV methotrexate in place of oral MTX and 6-MP(augmented BFM). DELAYED INTENSIFICATION : DELAYED INTENSIFICATION This phase consists of two parts: Re-induction and re-consolidation.It is 2- months long, during which the same induction and consolidation drugs are administered. Use of DI improved EFS in high risk patients(Gaynon et al, Leukemia 2000). Using two courses of DI in intermediate risk patients improved 6-year EFS from 79% to 89% (Lange et al, Blood 2002). This strategy is now under investigation by CCG for high risk patients. MAINTENANCE : MAINTENANCE This stage includes daily 6-MP, weekly oral methotrexate and monthly pulses of VCR and prednisone or dexamethasone. CNS prophylaxis is provided by giving IT MTX every 3 months for those who did not receive CNS radiation. CURRENT KFSH PROTOCOL : CURRENT KFSH PROTOCOL Current KFSH protocol is based on CCG 1882 protocol which is in turn based on standard BFM treatment with one delayed intensification. T-cell leukemia is treated on a different more intensive protocol. Patients with B-cell lineage who have unfavorable translocations{(9,22),(4,11),(1,19)} or MLL gene rearrangements are treated on the T-cell protocol.Those with (9,22),(4,11), bi-phenotypic leukemia and MLL rearrangements are sent for BMT if they have a donor. CURRENT KFSH PROTOCOL : CURRENT KFSH PROTOCOL CNS radiation is given to those who have CNS disease at diagnosis and to those who are older than 10 years or those younger with more than 100,000 WBC at diagnosis. Definition of CNS leukemia includes those who have CSF blasts even if CSF WBC is less than 5/hpf. No stratification based on initial response to therapy(Day 7 or D14 marrow). SUGGESTED CHANGES TO CURRENT PROOTOCOL : SUGGESTED CHANGES TO CURRENT PROOTOCOL Using the NCI criteria in defining high risk and low risk, regardless of phenotype. Using CCG definition of CNS leukemia. Using an augmented BFM regimen for those with slow early response (SER) as defined by M3 marrow at Day 7 of induction. Omitting CNS radiation to early responders to therapy regardless of age and WBC at diagnosis. RATIONALE FOR CHANGES : RATIONALE FOR CHANGES 1) CCG experience has shown that the outcome of T-cell ALL is similar to B-cell ALL, when intensive BFM therapy is used, once adjustment for age and WBC at diagnosis is made.The CCG 1800 series of studies resulted in 5-year of 75%, which is not significantly different from B-cell patients (Uckun et al, Blood 1998). RATIONALE FOR CHANGES : RATIONALE FOR CHANGES 2) CNS leukemia definition: A review for CCG data showed that 5-year EFS is similar for those with CSF blasts by centrifuging but less than 5 WBC when compared with those who did not have CSF blasts(Tubergen et al, JCO 1994).This review included more than 1500 patients. RATIONALE FOR CHANGES : RATIONALE FOR CHANGES 3)Augmented treatment for those who are SER at Day 7: A CCG randomized trial resulted in a 5-year EFS of 75% for those who received augmented BFM therapy and 55% for those who received standard therapy(p=0.001).The difference was more pronounced in those between 1-9 years and WBC of at least 50,000.(Nachman et al, NJM 1998). RATIONAL FOR CHANGES : RATIONAL FOR CHANGES 4)Omitting CNS radiation for RER: CCG 1882 showed that intensive treatment with intrathecal MTX utilized in BFM standard therapy achieves similar CNS protection and EFS as cranial radiation in patients with high risk ALL who are RER (Gaynon et al, Leukemia 2000).

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