Outcomes of a Randomized Trial of Hyperfractionated Cranial Radiation Therapy for Treatment of High-Risk Acute Lymphoblastic Leukemia: Therapeutic Efficacy and Neurotoxicity

Waber, Deborah P.; Silverman, Lewis B.; Catania, Lori; Mautz, William J.; Rué, Montserrat; Gelber, Richard D.; Levy, Donna E.; Goldwasser, Meredith A.; Adams, Heather; Dufresne, Annie; Metzger, Victoria; Romero, Ivonne; Tarbell, Nancy J.; Dalton, Virginia; Sallan, Stephen E.

doi:10.1200/jco.2004.10.173

Cited by 39 publications

(31 citation statements)

References 23 publications

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Section: Discussionmentioning

confidence: 99%

“…Especially in children and young adults, there are late effects of IT chemotherapy and CRT on cognition and growth. 42,43 Therefore, an orally available drug that can inhibit leukemia cell growth in the CNS without adverse effects is desirable.Because of its structural similarity to imatinib mesylate, which is a substrate for P-gp, 30 we first investigated whether INNO-406 was also a substrate for P-gp. The present study clearly demonstrated that INNO-406, like imatinib mesylate, is a substrate for P-gp ( Figure 1B-F).…”

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confidence: 99%

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INNO-406, a novel BCR-ABL/Lyn dual tyrosine kinase inhibitor, suppresses the growth of Ph+ leukemia cells in the central nervous system, and cyclosporine A augments its in vivo activity

Yokota

Kimura

Masuda

et al. 2006

Blood

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IntroductionImatinib mesylate (Gleevec; imatinib [Glivec]; formerly STI571), a specific inhibitor of ABL tyrosine kinase, is efficacious in treating Philadelphia chromosome-positive (Ph ϩ ) leukemias such as chronic myeloid leukemia (CML) and Ph ϩ acute lymphoblastic leukemia (ALL). 1,2 Within a few years of its introduction to the clinic, imatinib mesylate had dramatically altered the first-line therapy for CML, because it was found that most patients with newly diagnosed CML in the chronic phase (CP) achieved durable responses when treated with imatinib mesylate. 3 However, a small percentage of these patients, as well as most patients with advanced-phase CML and Ph ϩ ALL, relapse on imatinib mesylate therapy. 2,4 Several mechanisms of refractoriness and relapse have been reported, including point mutations within the ABL kinase domain, amplification of the bcr-abl gene, overexpression of bcr-abl mRNA, [5][6][7][8] increased drug efflux via a process mediated by P-glycoprotein (P-gp), 9 and activation of the Src-family protein Lyn. [10][11][12] There has recently been an increase in the numbers of reported cases of isolated central nervous system (CNS) relapse in which mainly patients with CML-blast crisis (BC) and Ph ϩ ALL who continued to have complete cytogenetic responses (CCgR) developed an extramedullary BC in the CNS. [13][14][15][16][17][18][19][20][21][22] Leis et al 23 reported that isolated CNS relapse occurred in 5 (20.8%) of 24 patients whose protocols included imatinib mesylate treatment, whereas Pfeifer et al 24 reported that CNS leukemia developed in 13 (12.1%) of 107 patients with Ph ϩ ALL. Isolated CNS relapse may be due to a limited penetration of imatinib mesylate into the cerebrospinal fluid (CSF), because it has been shown that concentrations of imatinib mesylate in the CSF are 1 to 2 orders of magnitude lower than the corresponding plasma levels. [24][25][26][27] Brain endothelial cells are characterized by their barrier properties, including tight junctions and various selective transporters. One of the transporters in the BBB, P-gp, which is expressed at the luminal side of the endothelial cells of the capillaries in the brain, plays an important role in drug efflux from the brain. Preclinical in vitro and in vivo studies have shown that imatinib mesylate is a substrate for P-gp, so that P-gp limits the distribution of imatinib mesylate to the brain. 28,29 The CNS can thereby become a sanctuary site of relapse in patients who are on prolonged imatinib mesylate therapy.To overcome resistance to imatinib mesylate, we recently developed a specific dual BCR-ABL/Lyn inhibitor, , which is 25 to 55 times more potent than imatinib mesylate in vitro and at least 10 times more potent than The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. Materials and methods Reagents ...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

INNO-406, a novel BCR-ABL/Lyn dual tyrosine kinase inhibitor, suppresses the growth of Ph+ leukemia cells in the central nervous system, and cyclosporine A augments its in vivo activity

Yokota

Kimura

Masuda

et al. 2006

Blood

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“…The results of the HR radiation randomization have been reported previously. 10 Nonrandomized changes to Protocol 95-01, also designed to reduce toxicity compared with previous protocols, included a reduction in the number of doses of asparaginase during the consolidation phase (20 instead of 30 consecutive weekly doses) and a reduction in the cumulative dose of doxorubicin for HR patients (300 mg/m 2 instead of 360 mg/m 2 ). In addition, National Cancer Institute (NCI) age and leukocyte criteria were applied prospectively in Protocol 95-01.…”

Section: Introductionmentioning

confidence: 99%

Results of the Dana-Farber Cancer Institute ALL Consortium Protocol 95-01 for children with acute lymphoblastic leukemia

Moghrabi

Levy

Asselin

et al. 2006

Blood

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369

277

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The Dana-Farber Cancer Institute (DFCI) Childhood ALL Consortium Protocol 95-01 was designed to minimize therapy-related morbidity for children with newly diagnosed ALL without compromising efficacy. Patients participated in randomized comparisons of (1) doxorubicin given with or without dexrazoxane, a cardioprotectant (high-risk patients), (2) intensive intrathecal chemotherapy and cranial radiation (standard-risk patients), and (3) Erwinia and Escherichia coli asparaginase (all patients). Between 1996 and 2000, 491 patients (aged 0-18 years) were enrolled (272 standard risk and 219 high risk). With a median of 5.7 years of followup, the estimated 5-year event-free survival (EFS) for all patients was 82% ؎ 2%. Dexrazoxane did not have a significant impact on the 5-year EFS of high-risk patients (P ‫؍‬ .99), and there was no significant difference in outcome of standardrisk patients based on type of central nervous system (CNS) treatment (P ‫؍‬ .26).Compared with E coli asparaginase, Erwinia asparaginase was associated with a lower incidence of toxicity (10% versus 24%), but also an inferior 5-year EFS (78% ؎ 4% versus 89% ؎ 3%, P ‫؍‬ .01). We conclude that (1) dexrazoxane does not interfere with the antileukemic effect of doxorubicin, (2) intensive intrathecal chemotherapy is as effective as cranial radiation in preventing CNS relapse in standard-risk patients, and (3) onceweekly Erwinia is less toxic than E coli asparaginase, but also less efficacious.

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“…22 A randomized trial showed that hyperfractionated (twice daily) cranial irradiation failed to reduce neurocognitive late effects and might have compromised antileukemic efficacy, as compared to conventionally dosed radiation. 23 Two pediatric and at least two adult trials have tested the feasibility of omitting cranial irradiation in all patients. 12,[24][25][26] In the pediatric trials, the cumulative risks of isolated CNS relapse were 4.2% and 3.0%, and the rates of any CNS relapse (including combined CNS and hematological relapse) were 8.3% and 6.0%.…”

Section: Cranial Irradiationmentioning

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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Outcomes of a Randomized Trial of Hyperfractionated Cranial Radiation Therapy for Treatment of High-Risk Acute Lymphoblastic Leukemia: Therapeutic Efficacy and Neurotoxicity

Abstract: HFX provides no benefit in terms of cognitive late effects and may compromise antileukemic efficacy. HFX should not be substituted for conventionally dosed CRT in children who require radiation therapy for treatment of acute lymphoblastic leukemia.

Cited by 39 publications

References 23 publications

INNO-406, a novel BCR-ABL/Lyn dual tyrosine kinase inhibitor, suppresses the growth of Ph+ leukemia cells in the central nervous system, and cyclosporine A augments its in vivo activity

INNO-406, a novel BCR-ABL/Lyn dual tyrosine kinase inhibitor, suppresses the growth of Ph+ leukemia cells in the central nervous system, and cyclosporine A augments its in vivo activity

Results of the Dana-Farber Cancer Institute ALL Consortium Protocol 95-01 for children with acute lymphoblastic leukemia

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

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