Intrathecal triple therapy decreases central nervous system relapse but fails to improve event-free survival when compared with intrathecal methotrexate: results of the Children's Cancer Group (CCG) 1952 study for standard-risk acute lymphoblastic leukemia, reported by the Children's Oncology Group

Matloub, Yousif; Lindemulder, Susan; Gaynon, Paul S.; Sather, Harland N.; La, Marzano; Broxson, Emmett; Yanofsky, Rochelle; Hutchinson, Raymond J.; Heerema, Nyla A.; Nachman, James B.; Blake, Marilyn; Wells, Linda; Sorrell, April; Masterson, Margaret; Kelleher, John F.; Stork, Linda C.

doi:10.1182/blood-2005-12-011809

Cited by 113 publications

(71 citation statements)

References 66 publications

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“…Pui et al 41 have shown that therapeutic escalation by TIT in ALL significantly reduces the risk of CSF relapse (165 patients, estimated risk 1.2%). However, Matloub et al 42 showed that, although the number of CNS relapses was lower in the TIT group relative to the group treated with simple MTX IT, EFS was similar because of more frequent bone marrow relapses in the TIT group.…”

Section: Discussionmentioning

confidence: 99%

Age and high-dose methotrexate are associated to clinical acute encephalopathy in FRALLE 93 trial for acute lymphoblastic leukemia in children

et al. 2006

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The objective of the study was to assess acute neurotoxicity associated with triple intrathecal therapy (TIT)7high-dose methotrexate (HD MTX) in children with acute lymphoblastic leukemia (ALL). 1395 children were enrolled on FRALLE 93 protocol from 1993 to 1999. Lower-risk group (LR, n ¼ 182) were randomized to weekly low-dose MTX at 25 mg/m 2 /week (LD MTX, n ¼ 81) or HD MTX at 1.5 g/m 2 /2 weeks Â 6 (n ¼ 77). Intermediate-risk group (IR, n ¼ 672) were randomized to LD MTX (n ¼ 290) or HD MTX at 8 g/m 2 /2 weeks Â 4 (n ¼ 316). Higherrisk group (HR, n ¼ 541) prednisone-responder patients received LD MTX and cranial radiotherapy. HR group steroid resistant cases were grafted (autologous or allogenic). TIT (MTX, cytarabine and methylprednisolone) was given every 2 weeks during 16-18 weeks and every 3 months during maintenance therapy in LR and IR patients. 52 patients (3.7%) developed neurotoxicity. Isolated seizures: n ¼ 15 (1.1%), peripheral and spinal neuropathy: n ¼ 17 (1.2%) and encephalopathy: n ¼ 20 (1.4%). Age 410 years was significantly associated with neurotoxicity (P ¼ 0.01) and use of HD MTX is associated with encephalopathy (P ¼ 0.03). Sequels are reported respectively in 60 and 33% of spinal neuropathy and encephalopathy cases. Current strategies tailoring risk of neurological sequels has to be defined.

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Section: Discussionmentioning

confidence: 99%

Age and high-dose methotrexate are associated to clinical acute encephalopathy in FRALLE 93 trial for acute lymphoblastic leukemia in children

et al. 2006

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“…30 Recently, however, a randomized study was performed to compare the efficacy of triple intrathecal therapy with that of intrathecal methotrexate only. 16 In that trial, triple intrathecal therapy reduced the frequency of isolated CNS relapse but unexpectedly was associated with an increased frequency of bone marrow and testicular relapse, leading to an inferior survival rate overall. One explanation for this seemingly paradoxical finding is that "isolated" CNS relapse is an early manifestation of systemic relapse, and that the better CNS control secured with triple intrathecal therapy versus intrathecal methotrexate favors overt leukemic relapse in other sites.…”

Section: Intrathecal Therapymentioning

confidence: 99%

“…7 It is well recognized that the impact of many prognostic factors can be lessened or eliminated altogether with intensified treatment. For example, CNS2 status (the presence of leukemic cells in a cerebrospinal fluid sample that contains fewer than 5 WBCs/µL) was associated with an increased risk of CNS relapse in many but not all clinical trials (Table 1), [8][9][10][11][12][13][14][15][16] apparently because of differences in the efficacy of systemic and CNS-directed therapy among the study groups. Likewise, the increased risk of CNS relapse and poor event-free survival associated with traumatic lumbar puncture with blasts in cerebrospinal fluid 10,14,17 can be overcome by more effective therapy ( Table 2).…”

Section: Risk Factors For Cns Relapsementioning

confidence: 99%

Central Nervous System Disease in Acute Lymphoblastic Leukemia: Prophylaxis and Treatment

Pui

2006

Hematology

105

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Improved treatment for acute lymphoblastic leukemia (ALL) has virtually eliminated testicular relapse. However, the control of central nervous system (CNS) leukemia remains a therapeutic challenge in childhood ALL, partly because of the late complications arising from cranial irradiation. In most current pediatric protocols, cranial irradiation (12 to 18 Gy) is given to 5% to 25% of patients—those with T-cell ALL, overt CNS disease (CNS3 status) or high-risk cytogenetics. CNS control is a less urgent concern in adults with ALL, in whom systemic relapse remains the major problem. With current approaches, approximately 2% to 10% of patients can be expected to develop CNS relapse. Children with B-cell precursor ALL who have a late CNS relapse (after an initial remission of 18 months or more) and did not receive cranial irradiation have an excellent outcome after retrieval therapy, with a 5-year event-free survival (EFS) rate approaching that in newly diagnosed patients. Innovative treatment options are needed for children who develop CNS relapses after a short initial remission or after receiving cranial irradiation, and in any adults with CNS leukemia at diagnosis or relapse.

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“…We evaluated neurocognitive functioning in patients previously randomly assigned to IT methotrexate versus triple IT therapy on legacy CCG 1952, from which Matloub et al 8 analyzed event-free survival and overall survival outcomes. We hypothesized that triple IT therapy is associated with greater neurocognitive impairment than IT methotrexate, especially in processing speed, attention, memory, and visual motor integration, and that younger age and female sex affect the association between IT preparation and neurocognitive functioning.…”

Section: Journal Of Clinical Oncology O R I G I N a L R E P O R T V Omentioning

confidence: 99%

“…In a Children's Cancer Group (CCG) study of 1,018 patients with childhood ALL, Matloub et al 8 concluded that triple IT therapy was associated with a 6-year cumulative incidence of isolated CNS relapse of 3.4% Ϯ 1.0% compared with 5.9% Ϯ 1.2% for IT methotrexate (P ϭ .004), but the therapies had similar event-free survival rates. Interestingly, triple IT…”

Section: Introductionmentioning

confidence: 99%

Comparison of Neurocognitive Functioning in Children Previously Randomly Assigned to Intrathecal Methotrexate Compared With Triple Intrathecal Therapy for the Treatment of Childhood Acute Lymphoblastic Leukemia

Kadan‐Lottick

Brouwers

Breiger

et al. 2009

JCO

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Purpose For the majority of children with acute lymphoblastic leukemia (ALL), CNS prophylaxis consists of either intrathecal (IT) methotrexate or triple IT therapy (ie, methotrexate with both cytarabine and hydrocortisone). The long-term neurotoxicities of these two IT strategies have not yet been directly compared. Patients and Methods In this multisite study, 171 children with standard-risk ALL, age 1 to 9.99 years at diagnosis, previously randomly assigned to IT methotrexate (n = 82) or to triple IT therapy (n = 89) on CCG 1952, underwent neurocognitive evaluation by a licensed psychologist at a mean of 5.9 years after random assignment. Results Patients who received IT methotrexate had a mean Processing Speed Index that was 3.6 points lower, about one fourth of a standard deviation, than those who received triple IT therapy (P = .04) after analysis was adjusted for age, sex, and time since diagnosis. Likewise, 19.5% of children in the IT methotrexate group had a Processing Speed Index score in the below-average range compared with 6.9% in the triple IT therapy group (P = .02). Otherwise, the groups performed similarly on tests of full-scale intelligence quotient, academic achievement, attention/concentration, memory, and visual motor integration. The association of treatment with measures of cognitive functioning was not modified by sex or age at diagnosis. In the post-therapy period, there were no group differences in special education services, neurologic events, or use of psychotropic medications. Conclusion This study did not show any clinically meaningful differences in neurocognitive functioning between patients previously randomly assigned to IT methotrexate or triple IT therapy except for a small difference in processing speed in the IT methotrexate group.

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Intrathecal triple therapy decreases central nervous system relapse but fails to improve event-free survival when compared with intrathecal methotrexate: results of the Children's Cancer Group (CCG) 1952 study for standard-risk acute lymphoblastic leukemia, reported by the Children's Oncology Group

Cited by 113 publications

References 66 publications

Age and high-dose methotrexate are associated to clinical acute encephalopathy in FRALLE 93 trial for acute lymphoblastic leukemia in children

Age and high-dose methotrexate are associated to clinical acute encephalopathy in FRALLE 93 trial for acute lymphoblastic leukemia in children

Central Nervous System Disease in Acute Lymphoblastic Leukemia: Prophylaxis and Treatment

Comparison of Neurocognitive Functioning in Children Previously Randomly Assigned to Intrathecal Methotrexate Compared With Triple Intrathecal Therapy for the Treatment of Childhood Acute Lymphoblastic Leukemia

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