Phase I Study of Bortezomib Combined With Chemotherapy in Children With Relapsed Childhood Acute Lymphoblastic Leukemia (ALL): A Report From the Therapeutic Advances in Childhood Leukemia (TACL) Consortium

Pediatric Hematology and Oncology, Children's Hospitals and Clinics of Minnesota, St. Paul, Minnesota 55102, USA.
Pediatric Blood & Cancer (Impact Factor: 2.39). 08/2010; 55(2):254-9. DOI: 10.1002/pbc.22456
Source: PubMed


Outcomes remain poor for children after relapse of acute lymphoblastic leukemia (ALL), especially after early marrow relapse. Bortezomib is a proteasome inhibitor with in vitro synergy with corticosteroids and clinical activity in human lymphoid malignancies.
This is a Phase I study of escalating doses bortezomib administered days 1, 4, 8, and 11, added to 4-drug induction chemotherapy with vincristine, dexamethasone, pegylated L-asparaginase, and doxorubicin (VXLD) in children with relapsed ALL.
Ten patients were enrolled, five in first marrow relapse, and five in second relapse. Four patients were enrolled at dose level 1 (bortezomib 1 mg/m(2)). One patient was not evaluable for toxicity because of omitted dexamethasone doses. No dose-limiting toxicity (DLT) was observed. Six patients were enrolled at dose level 2 (bortezomib 1.3 mg/m(2)). One patient had dose-limiting hypophosphatemia and rhabdomyolysis after 1 dose of bortezomib, and died from a diffuse zygomyces infection on day 17. Five additional patients were enrolled with no subsequent DLTs. As planned, no further dose escalation was pursued. The regimen had predictable toxicity related to the chemotherapy drugs. Two patients had mild peripheral neuropathy (grades 1 and 2). Six of nine evaluable patients (67%) achieved a complete response (CR), and one had a bone marrow CR with persistent central nervous system leukemia.
The combination of bortezomib (1.3 mg/m(2)) with VXLD is active with acceptable toxicity in pretreated pediatric patients with relapsed ALL. We are expanding the 1.3 mg/m(2) cohort for a phase II estimate of response. Study registered at (

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Available from: Bruce Bostrom, Apr 14, 2014
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    • "Promising results have been achieved from a phase II clinical trial in adult patients with relapsed or refractory indolent lymphoma [6]. In a recent phase I clinical study in relapsed childhood acute lymphatic leukemia, bortezomib was found to be efficacious when combined with traditional chemotherapeutic drugs [7]. "
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    ABSTRACT: Background With increased long-term survivors of childhood cancer patients, therapy-associated infertility has become one of the most common late side-effects and significantly affects their life-quality. Therefore, evaluation of anti-cancer agents on male reproduction and infertility prevention are urgently demanding. The proteasome inhibitor bortezomib has been launched in clinical trials for childhood cancers, however, its potential side effects on reproduction have so far been neither investigated experimentally nor reported in treated children. Thus the present study is designed to explore the impact of bortezomib on male reproductive function and to gain insights into how bortezomib exerts its adverse effects on man gonad, thereby providing pediatric oncologists relevant information. Methods 35 day-old male mice were treated with one 11-day cycle of bortezomib and then sacrificed 2 days, 45 days, or 6 months later. A mating study was performed in the group followed for 6 months, and their pups were analyzed on postnatal day 50. Serum follicle-stimulating hormone (FSH) and testicular testosterone levels were measured. Testicular morphology was evaluated by light- and electron microscopy, and the underlying mechanisms and pathways of testis damage were investigated. Results Testicular damage was visible already 2 days after stopping bortezomib and increased in severity by day 45. Then 80% of seminiferous tubules exhibited hypospermatogenesis with arrest at the levels of spermatogonia, spermatocytes and round spermatids. Germ cells were specifically targeted by bortezomib as evidenced by increased apoptosis mediated through activation of p53 and caspases. Even six months after the bortezomib treatment, testis weight, sperm concentration and seminiferous tubule length remained at a decreased level, indicating that spermatogenesis and tubular outgrowth could not fully recover. Combined with persistently increased serum levels of FSH in these mice, our results demonstrate that bortezomib can have long-term effects on testicular function, although fertility of bortezomib-exposed males remained and their offspring looked healthy. Conclusion Bortezomib treatment causes long-term gonadal dysfunction in male mice. Careful monitoring of gonadal function in male childhood cancer patients treated with bortezomib is thus strongly recommended.
    Full-text · Article · Jun 2014 · Molecular Cancer
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    • "Clinical trials conducted to date suggest that bortezomib may only yield minor clinical benefits in leukemia patients when administered as a single drug (Orlowski et al., 2002; Cortes et al., 2004). However, bortezomib enhances the effect of many conventional therapies and may overcome resistance to conventional anticancer drugs, and the effects in combination studies appear promising (Hideshima et al., 2001; Mitsiades et al., 2003; Nikrad et al., 2005; Messinger et al., 2010). However , potential biologic markers of susceptibility to proteasome inhibitors are lacking. "
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    ABSTRACT: Bortezomib is a highly selective inhibitor of the 26S proteasome and has been approved for clinical use in the treatment of relapsing and refractory multiple myeloma and mantle cell lymphoma. Clinical trials are also underway to assess the role of bortezomib in several other human malignancies including leukemia. However, the mechanism(s) by which bortezomib acts remain to be fully understood. Here, we studied the molecular requirements of bortezomib-induced apoptosis using the human T cell leukemic Jurkat cells stably transfected with or without shRNA against apoptotic protease-activating factor-1 (Apaf-1). The Apaf-1-deficient Jurkat T cells were resistant to bortezomib-induced apoptosis, as assessed by caspase-3 activity, PARP cleavage, phosphatidylserine externalization, and hypodiploid DNA content. In contrast, Apaf-1-deficient cells were sensitive to Fas-induced apoptosis. Bortezomib induced an upregulation of the pro-apoptotic protein Noxa, loss of mitochondrial transmembrane potential, and release of cytochrome c in cells expressing or not expressing Apaf-1. Transient silencing of Apaf-1 expression in RPMI 8402 T cell leukemic cells also diminished bortezomib-induced apoptosis. FADD-deficient Jurkat cells were resistant to Fas-mediated apoptosis yet remained sensitive to bortezomib. Our results show that bortezomib induces apoptosis by regulating pathways that are mechanistically different from those activated upon death receptor ligation. Furthermore, in silico analyses of public transcriptomics databases indicated elevated Apaf-1 expression in several hematological malignancies, including acute lymphoblastic and myeloid leukemia. We also noted variable Apaf-1 expression in a panel of samples from patients with acute lymphoblastic leukemia. These results suggest that the expression of Apaf-1 may be predictive of the response to proteasome inhibition.
    Full-text · Article · Oct 2012 · Molecular pharmacology
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    • "Bortezomib is currently included in several Phase II clinical trials for treatment of acute lymphoblastic leukemia (updated at the site: Several of the ongoing trials also include a glucocorticoid in the treatment scheme (Messinger et al., 2010). Results from Phase I trials for childhood leukemia indicate that Bortezomib could be more effective in combination schemes, than as a single agent (Horton et al., 2007). "
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    ABSTRACT: Twenty years ago a proteasome inhibitor was suggested as therapy for glucocorticoid-resistant multiple myeloma, a disease that involves terminally differentiated B cells. Since then, research has proven that it has utility on a number of tumors resistant to chemotherapy. Hematologic malignancy, however, often involves lesser differentiated cells, which have a high potential to modulate their intrinsic machinery and thereby activate alternative rescue pathways. A corresponding multiplicity of therapies is not always practical. One approach to conditions with heterogeneous physiology is to identify key biochemical mediators, thereby reducing the number of treatment targets. Results from several ongoing studies indicate convergence of genomically diverse signal pathways to a limited number of key downstream regulators of apoptosis. Convergence of pathways can be exploited to address the problem of genetic heterogeneity in acute leukemia: this would mean treating multiple molecular aberrations with fewer drugs and enhanced therapeutic benefit.
    Full-text · Article · Apr 2012 · Molecular and Cellular Endocrinology
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