Philadelphia chromosome in relapsed childhood acute lymphoblastic leukemia: a matched-pair analysis. Berlin-Frankfurt-Münster Study Group.

Beyermann, Birgit; Adams, HP; Henze, Günter

doi:10.1200/jco.1997.15.6.2231

Cited by 35 publications

(22 citation statements)

References 24 publications

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“…Clinical studies have shown that the Philadelphia chromosome translocation, t(9;22)(q34;q11), is an independent risk factor in childhood ALL (23). At the molecular level this results in the fusion of Bcr and Abl sequences leading to a chimeric mRNA and the Bcr-Abl protein.…”

Section: Discussionmentioning

confidence: 99%

Effects of 17-Allylamino-17-Demethoxygeldanamycin (17-AAG) on Pediatric Acute Lymphoblastic Leukemia (ALL) with Respect to Bcr-Abl Status and Imatinib Mesylate Sensitivity

2005

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As more and more effective targeted therapeutics have been developed to treat adults with cancer, it is of critical importance to devise appropriate in vitro experimental models to study their use in pediatric patients. Acute lymphoblastic leukemia (ALL) with Bcr-Abl translocation is one of the most difficult to treat and deadly diseases in children. The targeted kinase inhibitor imatinib mesylate has been shown to induce an initial response but resistance often develops. Recently, the geldanamycin family of antibiotics has been found to induce apoptosis in many malignant cells, including adult CML and AML. We describe experiments in which 17-allylamino-17-demethoxygeldanamycin (17-AAG) was evaluated in the context of Bcr-Abl and resistance to imatinib mesylate. Pediatric ALL cell lines with varying Bcr-Abl status and imatinib mesylate sensitivity were generated and their growth inhibition by 17-AAG was studied in vitro. Western blots were used to follow the changes in proteins that correlate with cell survival. Results show that apoptosis was induced in all lines with an increased 50% inhibitory concentration (IC 50 ) for BcrAbl positive but imatinib mesylate-resistant cells. Addition of 17-AAG greatly increased imatinib sensitivity in vitro. A decrease in p53, survivin, Her2/neu, and WT1 was seen in cells that expressed these proteins. With some notable exceptions, when combined with 17-AAG, the IC 50 of most of the common chemotherapeutic agents decreased. We describe an experimental approach to investigate the complex interaction between Bcr-Abl status, imatinib mesylate sensitivity, and 17-AAG in pediatric ALL. Information from such an approach will provide means to devise combined treatment approaches and to follow their effectiveness in vitro. Despite the impressive therapeutic advances of the last 30 years, a quarter of the children with ALL still die from their disease (1). Attempts to cure the patients at greatest risk of treatment failure have included intensification of chemotherapeutic regimens and the use of bone marrow transplantation. In recent years, an increasing knowledge of the molecular mechanisms involved in leukemic cell growth has shifted the focus of new antileukemic drug development from empirical antineoplastics to agents that act on specific molecular targets. Such targets include individual proteins that regulate signal transduction, apoptosis, and cell cycle progression and those that confer oncogenic potential such as Bcr-Abl (2).The Philadelphia chromosome is a product of a t(9;22)(q34;q11) translocation that fuses the c-Abl gene on chromosome 9 with the Bcr gene on chromosome 22 (3). This abnormality is observed in 3-5% of children with ALL, and it is one of the most difficult to treat among all childhood leukemias (1,4). The use of the novel kinase inhibitor imatinib mesylate (Gleevec, STI571; Novartis, Basel, Switzerland) has shown effectiveness in relapsed Phϩ ALL (5), but adult studies have shown significant potential for recurrence (6).It is widely known that the survival an...

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Section: Discussionmentioning

confidence: 99%

Effects of 17-Allylamino-17-Demethoxygeldanamycin (17-AAG) on Pediatric Acute Lymphoblastic Leukemia (ALL) with Respect to Bcr-Abl Status and Imatinib Mesylate Sensitivity

2005

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“…Among the 14 patients with no hematological relapse (74%), eight remained BCR-ABL negative for up to 4 years and six had no molecular follow-up (five of them died in the first 3 months after HSCT). Five patients (26%) experienced a relapse, all after transient negativity of RT-PCR, and BCR-ABL transcript reappearance at 3,8,17,20, and 43 months. Three patients were treated with chemotherapy without interferon-a, but with DLI in two cases.…”

Section: Minimal Residual Disease Follow-upmentioning

confidence: 99%

“…There were 63 males and 58 females who had received HSCT in 27 centers. Two groups were analyzed: 102 adults with a median age of 38 years (range, 18-53) and 19 children with a median age of 8 years (range, [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18]. Median white blood cell count (WBC) was 19 Â 10 9 /l (range, 1-500) for the entire population, 36 Â 10 9 /l (range, 1-382) in children, and 18 Â 10 9 /l (range, 1-500) in adults.…”

Section: Patient Characteristicsmentioning

confidence: 99%

“…5 Ph-positive ALL is a subgroup of ALL with a poor prognosis in both children and adults. [6][7][8] After complete remission (CR) achievement, CR duration is short in patients treated with conventional intensive chemotherapy, at least in adults. However, it has recently been reported that the disease can be controlled by chemotherapy alone in a subset of children with a low leukocyte count at diagnosis.…”

Section: Introductionmentioning

confidence: 99%

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A potential graft-versus-leukemia effect after allogeneic hematopoietic stem cell transplantation for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: results from the French Bone Marrow Transplantation Society

Esperou

Cayuela

et al. 2003

Bone Marrow Transplant

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“…[1][2][3] Patients with Ph+ ALL have an extremely poor prognosis for long-term survival. 4 Although the ability to achieve a first complete remission (CR) is not significantly reduced in Ph+ ALL, the durability of these remissions with standard and intensified chemotherapy regimens is extremely limited. 5 Allogeneic bone marrow transplantation (BMT) has been utilized as a post-induction therapy to try to improve disease-free survival (DFS) for these patients.…”

Section: Introductionmentioning

confidence: 99%

Long-term follow-up of 23 patients with Philadelphia chromosome-positive acute lymphoblastic leukemia treated with allogeneic bone marrow transplant in first complete remission

Snyder

Nademanee

et al. 1999

Leukemia

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Between 1984 and 1997, 23 consecutive patients with Philadelphia chromosome-positive acute lymphoblastic leukemia in first complete remission were treated with allogeneic bone marrow transplants from HLA-matched siblings. All patients but one were conditioned with fractionated total body irradiation (1320 cGy) and high-dose etoposide (60 mg/kg). One patient received high-dose cyclophosphamide instead of etoposide, and another patient received both drugs. Nine patients died following BMT, two from relapsed leukemia, and seven from transplant-related causes. The 3-year probabilities of disease-free survival and relapse are 65% and 12%, respectively. For patients transplanted after 1992, these probabilities are 81% (48-95%, 95% confidence interval) and 11% (2-50%), respectively. The relatively low relapse rate in this group of patients compared to published reports may reflect the enhanced antileukemic activity of etoposide in combination with FTBI compared to other conditioning regimens. The enhancement in overall survival for patients transplanted after 1992 may reflect improvements in supportive care, in particular, the prophylaxis of serious fungal and viral infections.

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Philadelphia chromosome in relapsed childhood acute lymphoblastic leukemia: a matched-pair analysis. Berlin-Frankfurt-Münster Study Group.

Cited by 35 publications

References 24 publications

Effects of 17-Allylamino-17-Demethoxygeldanamycin (17-AAG) on Pediatric Acute Lymphoblastic Leukemia (ALL) with Respect to Bcr-Abl Status and Imatinib Mesylate Sensitivity

Effects of 17-Allylamino-17-Demethoxygeldanamycin (17-AAG) on Pediatric Acute Lymphoblastic Leukemia (ALL) with Respect to Bcr-Abl Status and Imatinib Mesylate Sensitivity

A potential graft-versus-leukemia effect after allogeneic hematopoietic stem cell transplantation for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: results from the French Bone Marrow Transplantation Society

Long-term follow-up of 23 patients with Philadelphia chromosome-positive acute lymphoblastic leukemia treated with allogeneic bone marrow transplant in first complete remission

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