Current uses of monoclonal antibodies in the treatment of acute leukemia

Advances in the treatment of acute leukemia have been limited by both disease resistance and toxicity. Monoclonal antibodies have been used as a means of targeting therapy to malignant cells in the form of antibody-mediated cellular toxicity, radiation, or other cytotoxic agents. Anti-CD33 and anti-CD45 antibodies have been most extensively studied. Antibodies conjugated with either radioisotopes or cytotoxic moieties have been used as part of stem cell transplant regimens or as induction therapy in patients with relapsed acute myelogenous leukemia (AML), and have demonstrated antileukemic activity with acceptable toxicities.     

老年人急性髓系白血病治疗进展

 老年急性髓性白血病（AML）患者的预后在最近30年间没有明显改善,老年患者的特点限制了其耐受强烈化疗的能力并且导致更高的早期死亡率。老年AML患者很大一部分有既往血液学疾病史,其白血病细胞有预后不良的遗传学异常,表达多药耐药基因（MDR1）,这些特点导致对化疗耐药。近30年间研究、应用了许多方法。现对老年AML患者治疗研究进展作一综述。     

Induction of cytotoxic lymphocyte subsets against leukemia by stimulation with AML blasts

Although the application of interleukin-2 (IL-2) activated lymphocytes in immunotherapy of acute myelogenous leukemia (AML) is of therapeutic interest, the high resistance of AML blasts to lymphocyte iysis may represent an obstacle to this type of therapy. However, our data shows that the leukemia resistance can be conquered by concomitant culture of lymphocytes with IL-2 and AML blasts. This approach induces not only leukemia-dlrected cytotoxic cells, but also promotes their growth. Additionally, multiple cytotoxic lymphocyte populations with leukemia lyric activity are induced in AMIJIL-2 cultures. These include natural killer (NK) cells and subsets ofT cells with both the major histocompatibility complex (MHC)-restricted and MHC-nonrestricted cytotoxic function. Thus, this protocol, which is conducive to general stimulation of cellular immune responses against leukemia, may enhance the benefits of lymphocyte therapy.     

The role of gemtuzumab ozogamicin in the treatment of acute myeloid leukemia patients

Gemtuzumab Ozogamicin (GO) targets leukemia cells expressing CD33 by means of a monoclonal antibody conjugated to a cytotoxic agent, calicheamicin. GO has been approved in Japan as monotherapy for the treatment of patients with relapsed/refractory acute myeloid leukemia (AML)since 2005. GO administered as a single agent has resulted in overall response rates of about 30% in previously relapsed adult AML. Preliminary data indicate a potential role for GO also as a component of induction or consolidation regimen. Although caution is advised when administering GO within 115 days of a stem cell transplantation (SCT) procedure because of veno-occlusive disease, recent clinical studies overseas suggest that GO can be integrated into reduced-intensity conditioning therapy before allogeneic SCT in patients with relapsed AML. In order to reduce toxicity and improve efficacy, its optimal dose and schedule should be defined by large clinical trials.     

Drug resistance in clinical practice: Patterns of treatment failure in patients receiving systemic therapy for advanced breast cancer

Strategies for overcoming the causes of drug resistance should take account of the patterns of treatment failure seen in clinical practice. We have analysed the patterns of disease progression in 267 patients with advanced breast cancer receiving systemic therapy. First disease progression on therapy most commonly occurred in tissues involved by tumour at the commencement of treatment. However in 40% of patients, first documentation of disease progression included a tissue not previously known to contain metastatic disease. In only 3% of patients was this new tissue the central nervous system. This pattern of disease progression was not influenced by treatment type (i.e. endocrine or cytotoxic), tumour response to treatment, oestrogen receptor status, prior adjuvant cytotoxic treatment, or disease free interval. These results question the wisdom of always ceasing existing therapy and substituting new treatment when progressive disease is first documented.     

Eradication of leukemia stem cells as a new goal of therapy in leukemia.

Leukemias have traditionally been classified and treated on the basis of phenotypic characteristics, such as morphology and cell-surface markers, and, more recently, cytogenetic aberrations. These classification systems are flawed because they do not take into account cellular function. The leukemia cell population is functionally heterogeneous: it consists of leukemia stem cells (LSC) and mature leukemia cells that differentiate abnormally to varying extents. Like normal hematopoietic stem cells, LSCs are quiescent and have self-renewal and clonogenic capacity. Because they are quiescent, LSCs do not respond to cell cycle-specific cytotoxic agents used to treat leukemia and so contribute to treatment failure. These cells may undergo mutations and epigenetic changes, further leading to drug resistance and relapse. Recent data suggest that mature leukemia cells may acquire LSC characteristics, thereby evading chemotherapeutic treatment and sustaining the disease. Ongoing research is likely to reveal the molecular mechanisms responsible for LSC characteristics and lead to novel strategies for eradicating leukemia.     

Targeting the Proteasome in Refractory Pediatric Leukemia Cells: Characterization of Effective Cytotoxicity of Carfilzomib

Background

Leukemia accounts for 30% of all childhood cancers and although the survival rate for pediatric leukemia has greatly improved, relapse is a major cause of treatment failure. Therefore, the development and introduction of novel therapeutics to treat relapsed pediatric leukemia is urgently needed. The proteasome inhibitor bortezomib has been shown to be effective against adult hematological malignancies such as multiple myeloma and lymphoma, but is frequently associated with the development of resistance. Carfilzomib is a next-generation proteasome inhibitor that has shown promising results against refractory adult hematological malignancies.

Objective

Carfilzomib has been extensively studied in adult hematological malignancies, providing the rationale for evaluating proof-of-concept activity of carfilzomib in pediatric leukemia.

Methods

The effects of carfilzomib on pediatric leukemia cell lines and primary pediatric leukemia patient samples were investigated in vitro using the alamar blue cytotoxicity assay, western blotting, and a proteasome activity assay. Synergy with commonly used anticancer drugs was determined by calculation of combination indices.

Results

In vitro preclinical data show pharmacologically relevant concentrations of carfilzomib are cytotoxic to pediatric leukemia cell lines and primary pediatric leukemia cells. Target modulation studies validate the effective inhibition of the proteasome and induction of apoptosis. We also identify agents that have effective synergy with carfilzomib in these cells.

Conclusions

Our data provide pre-clinical information that can be incorporated into future early-phase clinical trials for the assessment of carfilzomib as a treatment for children with refractory hematological malignancies.

     

拓扑异构酶抑制剂治疗白血病的研究进展

 DNA拓扑异构酶是参与细胞基本活动的重要核酶,其抑制剂主要通过形成"DNA-药物-酶"三聚复合物干扰DNA的复制发挥抗肿瘤作用。重点阐述以拓扑异构酶Ⅰ为靶点的新药在白血病治疗中应用现况、拓扑异构酶表达水平与临床疗效及预后的关系和白血病细胞对拓扑异构酶抑制剂产生耐药的发生机制等方面研究进展。     

New antimetabolites in the treatment of human malignancies.

Several new antimetabolites have been evaluated in clinical trials in recent years. Those with the most promising activity include the structurally related purine analogs fludarabine, 2-chlorodeoxyadenosine, and 2'-deoxycoformycin. These compounds have shown impressive activity against a broad spectrum of indolent lymphoproliferative disorders, including hairy-cell leukemia, chronic lymphocytic leukemia, and low-grade non-Hodgkin's lymphomas. They may also be useful in the treatment of acute leukemias. In contrast, they lack activity against common solid tumors. They have been generally well tolerated in large clinical trials; however, each of them is myelosuppressive and immunosuppressive. It is unlikely that any one of these drugs, when used as a single agent, will provide optimal therapy for any disease other than, possibly, hairy-cell leukemia. Combinations with other cytotoxic agents and biologics are in development, and perhaps they will lead to more effective regimens in the future.     

Factor associated with failure to administer subsequent treatment after progression in the first-line chemotherapy in EGFR-mutant non-small cell lung cancer: Okayama Lung Cancer Study Group experience

Purpose

Early administration of both epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) monotherapy and cytotoxic chemotherapy is crucial for non-small cell lung cancer (NSCLC) patients harboring EGFR mutations. We investigated the effect of first-line administration of these therapies on subsequent therapy in NSCLC patients.

Methods

This study enrolled 63 consecutive patients with advanced EGFR-mutant NSCLC and good performance status (PS) and who underwent first-line EGFR-TKI therapy or standard cytotoxic chemotherapy and then had progressive disease, from 2007 to 2011. The ability of each patient to receive the other therapy after first-line treatment failure was assessed.

Results

In the first-line setting, 23 and 40 patients received EGFR-TKI therapy and cytotoxic chemotherapy, respectively. At relapse, the EGFR-TKI therapy group showed more frequent PS deterioration (p = 0.042) and greater likelihood of symptomatic central nervous system (CNS) relapse (p = 0.093) compared with the cytotoxic chemotherapy group. Nine (39 %) of 23 patients initially receiving EGFR-TKI therapy could not receive standard cytotoxic therapy after progression mainly due to symptomatic CNS relapse. Only one (3 %) of 40 initially treated with cytotoxic chemotherapy failed to receive subsequent EGFR-TKI therapy (p < 0.001). Multivariate analysis revealed a correlation between the first-line therapy and the failure to switch to the other therapy after disease progression (OR 48.605, p = 0.005).

Conclusion

In this study, patients who could not receive both EGFR-TKI therapy and cytotoxic chemotherapy in the early-line setting were included more in the first-line EGFR-TKI group, suggesting a potential risk associated with missing the timing of administration of subsequent therapy. Further investigation is warranted to detect their pretreatment clinical or molecular characteristics for development of a new treatment strategy specific for such subpopulation.     

Outpatient management of febrile neutropenia: time to revise the present treatment strategy

We reviewed medical literature on the efficacy and safety of outpatient versus hospital-based therapy of low-risk febrile neutropenia in adult cancer patients. A PubMed search for all studies evaluating the outpatient treatment of adults diagnosed with solid tumors who suffered from low-risk febrile neutropenia was completed; reference lists from identified articles also were used. In all, 10 trials were included in the analysis, which showed no significant difference in clinical failure rates and mortality for ambulatory regimens and standard hospital-based therapy. Subgroup analysis according to the type of fever episode showed no significant differences in clinical failure rates for fever of unknown origin and fever due to documented infections. Subgroup analyses in two independent trials identified an absolute neutrophil count < 100 cells/ mm3 as being predictive of outpatient treatment failure (P < 0.04). These findings need to be confirmed by further trials. Thus, outpatient management of adult cancer patients with low-risk febrile neutropenia is safe, effective, and comparable to standard hospital-based therapy. Patients at low risk are outpatients and are hemodynamically stable; they have no organ failure, they are able to take oral medications, and they do not suffer from acute leukemia. Low-risk prediction also may be based on the Multinational Association for Supportive Care in Cancer risk index.     

On the potential role of cyclosporin in the treatment of lymphoproliferative diseases

Lymphomas and leukemias, as cancers of the immune system, may still retain some susceptibility to regulatory mechanisms which govern the proliferation of their cells of origin. According to this concept, an enhanced immune suppression as induced by irradiation and chemotherapy may contribute to their cytotoxic effect in inducing and maintaining a remission of the disease. Cyclosporin selectively and reversibly inhibits activation and proliferation of both normal and neoplastic T lymphocytes. In-vitro experiments and preliminary clinical data from small uncontrolled studies indicate that cyclosporin might be a promising agent in the treatment of mycosis fungoides, Hodgkin's disease, acute leukemia, and possibly other lymphoproliferative disorders, but the experience is still limited and no definitive conclusions may be made. In addition to its direct effect on lymphocytes, cyclosporin reverses the resistance of cancer cells to several antineoplastic agents and may thus find its place in combination with chemotherapy. It is hoped that a more systematic basic and clinical research will help define the role of this new therapeutic approach.     

Cytotoxic drug-induced, p53-mediated upregulation of caspase-8 in tumor cells

Apoptosis resistance is crucially involved in cancer development and progression, represents the leading cause for failure of anticancer therapy and is caused, for example, by downregulation of proapoptotic intracellular signaling molecules such as caspase-8. We found that the cytotoxic drugs methotrexate (MTX) and 5-fluorouracil (5-FU) were both able to sensitize resistant tumor cells for induction of apoptosis by p53-mediated upregulation of caspase-8. Increase in caspase-8 messenger RNA and protein expression disabled tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced proliferation and restored sensitivity toward TRAIL-induced apoptosis which was inhibited by transfection of p53 decoy oligonucleotides, p53 shRNA and caspase-8 shRNA. Upregulation of caspase-8 and sensitization toward TRAIL-induced apoptosis was found both in a broad panel of tumor cell lines with downregulated caspase-8 and in TRAIL-resistant primary tumor cells of children with acute leukemia. Taken together, we have identified caspase-8 as an important p53 target gene regulated by cytotoxic drugs. These findings highlight a new drug-induced modulation of physiological apoptosis pathways, which may be involved in successful anticancer therapy using MTX and 5-FU in leukemia and solid tumors over decades.     

Methadone, commonly used as maintenance medication for outpatient treatment of opioid dependence, kills leukemia cells and overcomes chemoresistance

The therapeutic opioid drug methadone (d,l-methadone hydrochloride) is the most commonly used maintenance medication for outpatient treatment of opioid dependence. In our study, we found that methadone is also a potent inducer of cell death in leukemia cells and we clarified the unknown mechanism of methadone-induced cell killing in leukemia cells. Methadone inhibited proliferation in leukemia cells and induced cell death through apoptosis induction and activated apoptosis pathways through the activation of caspase-9 and caspase-3, down-regulation of Bcl-x(L) and X chromosome-linked inhibitor of apoptosis, and cleavage of poly(ADP-ribose) polymerase. In addition, methadone induced cell death not only in anticancer drug-sensitive and apoptosis-sensitive leukemia cells but also in doxorubicin-resistant, multidrug-resistant, and apoptosis-resistant leukemia cells, which anticancer drugs commonly used in conventional therapies of leukemias failed to kill. Depending on caspase activation, methadone overcomes doxorubicin resistance, multidrug resistance, and apoptosis resistance in leukemia cells through activation of mitochondria. In contrast to leukemia cells, nonleukemic peripheral blood lymphocytes survived after methadone treatment. These findings show that methadone kills leukemia cells and breaks chemoresistance and apoptosis resistance. Our results suggest that methadone is a promising therapeutic approach not only for patients with opioid dependence but also for patients with leukemias and provide the foundation for new strategies using methadone as an additional anticancer drug in leukemia therapy, especially when conventional therapies are less effective.     

Asparaginase in the treatment of non-ALL hematologic malignancies

Asparaginases are among the most effective agents against acute lymphoblastic leukemia (ALL) and are Food and Drug Administration-approved for the treatment of pediatric and adult ALL. However, the efficacy of these drugs for the treatment of other hematologic malignancies particularly acute myeloid leukemia is not well established. The mechanism of action of asparaginases has thought to be related to a swift and sustained reduction in serum l-asparagine, which is required for rapid proliferation of metabolically demanding leukemic cells. However, asparagine depletion alone appears not to be sufficient for effective cytotoxic activity of asparaginase against leukemia cells, because glutamine can rescue asparagine-deprived cells by regeneration of asparagine via a transamidation chemical reaction. For this reason, glutamine reduction is also necessary for full anti-leukemic activity of asparaginase. Indeed, both Escherichia coli and Erwinia chrysanthemi asparaginases possess glutaminase enzymatic activity, and their administrations have shown to reduce serum glutamine level by deamidating glutamine to glutamate and ammonia. Emerging data have provided evidence that several types of neoplastic cells require glutamine for the synthesis of proteins, nucleic acids, and lipids. This fundamental role of glutamine and its metabolic pathways for growth and proliferation of individual malignant cells may identify a special group of patients whose solid or hematologic neoplasms may benefit significantly from interruption of glutamine metabolism. To this end, asparaginase products deserve a second look particularly in non-ALL malignant blood disorders. Here, we review mechanisms of anti-tumor activity of asparaginase focusing on importance of glutamine reduction, pharmacology of asparaginase products, in vitro activities as well as clinical experience of incorporating asparaginase in therapeutic regimens for non-ALL hematologic malignancies.     

RNA干扰及其在白血病多药耐药方面的研究进展

 白血病化疗失败的主要原因是白血病细胞的多药耐药，这是困扰临床肿瘤化疗的难题之一。RNAi是新近发展起来的一种全新的基因治疗手段。与常用的反义RNA技术等其他基因方法相比，具有经济、高效、高度特异性、操作简便、快速等优点。该技术为白血病多药耐药的基础和临床研究开辟了新思路，也为新的分子诊断和分子治疗提供可能。     

难治性白血病诊治进展

 难治性白血病因其本身特性难达完全缓解和长期无病生存,始终是恶性血液病领域研究的热点和难点,国内外关于难治性白血病的诊断标准在不断调整,引起白血病难治高危的因素也在不断的被发现;新的分子标志,基因突变或某些基因高表达,如FLT3 跨膜区内部串联重复等,这些分子标志将决定急性白血病患者的预后。治疗难治性或复发性急性髓细胞性白血病仍然具有挑战性。多种新药正在开发和临床试验。临床许多新的治疗方法正在探讨。如应用耐药逆转剂、加强分子靶向治疗、改进造血干细胞移植和开发新药、组成新的化疗方案等;单克隆抗体和多肽疫苗与白血病相关抗原为治愈急性白血病带来了希望。     

Monoclonal antibody therapy of spontaneous AKR T-cell leukemia

We have previously shown that monoclonal antibodies against the Thy 1.1 differentiation antigen can inhibit the outgrowth of a lethal inoculum of transplanted AKR T-leukemic cells. In the present report we have extended these studies to examine antibody therapy of aged AKR/J mice with spontaneous leukemia. Infusion of anti-Thy 1.1 antibody in frankly leukemic mice led to uniform early mortality from cell lysis and agglutination. In contrast, anti-Thy 1.1 antibody therapy of mice in remission following treatment with cyclophosphamide prolonged remission duration (P less than 0.001) and modestly prolonged survival (P less than 0.01) compared to treatment with irrelevant antibody or chemotherapy alone. The major cause of failure was relapse of leukemia. In 85% (47 of 55) of cases relapse was due to cells that continued to express Thy 1.1, but in 15% of these relapsing animals all leukemic cells failed to express the target antigen. Our results suggest that monoclonal antibody against a normal T-cell antigen can add to the antileukemic effects obtained with chemotherapy alone. Nevertheless, the clinical benefit of unmodified antibody was modest, and antibodies conjugated to cytotoxic agents may be needed to overcome the limitations of unmodified antibodies.     

Recent advances in the treatment of adult T‐cell leukemia‐lymphomas

Recent advances in treatment for adult T‐cell leukemia‐lymphoma (ATL) are reviewed herein. It is currently possible to select a therapeutic strategy for ATL and predict prognosis by classification of patients by clinical subtypes and clinicopathological factors. Although the overall survival (OS) of patients with ATL has increased marginally because of advances in chemotherapy, further prolongation of survival might be difficult with conventional chemotherapy alone. Promising results have been reported for antiviral therapy using zidovudine and interferon‐α, and, indeed, antiviral therapy is currently the standard treatment for patients with ATL in western countries. Remarkably, the 5‐year OS rates are 100% for both the smoldering‐type and chronic‐type ATL. Recently, treatments for ATL have included allogeneic hematopoietic stem cell transplantation and molecular targeted therapies. Furthermore, the anti‐CCR4 monoclonal antibody mogamulizumab has been shown to have marked cytotoxic effects on ATL cells, especially in the leukemic type of ATL. In the lymphoma type of ATL, the response rate may be improved by combining mogamulizumab with chemotherapy. It should be recognized that prevention of infection from carriers of human T‐cell leukemia virus type‐I and transfer of the virus from mother to infant are crucial issues for the eradication of ATL.     

High-dose cytosine arabinoside as the initial treatment of poor-risk patients with acute nonlymphocytic leukemia: a Leukemia Intergroup Study

Sixty-seven patients with newly diagnosed acute nonlymphocytic leukemia (ANLL) who were considered to be poor candidates for treatment with cytosine arabinoside (ara-C)/anthracycline antibiotic therapy were treated with high-dose ara-C (HDara-C) remission induction therapy. Thirty-four of the 67 patients had a hematologic disorder before developing acute leukemia or had a history of exposure to marrow toxins, 23 patients were greater than 70 years old, and 10 patients had medical problems that were felt to be a contraindication to therapy with an anthracycline antibiotic. Forty-two percent of patients entered complete remission (CR), whereas 22% failed to enter remission because of persistent leukemia. Treatment was associated with substantial toxicity varying from nausea and vomiting to irreversible cerebellar toxicity. Thirty-four percent of patients died during therapy. Poor performance status, a low serum albumin, and a low platelet count were associated with death during remission induction therapy, whereas a high pretherapy leukemic cell mass and a large number of residual leukemic cells in the marrow after six days of therapy were associated with treatment failure due to persistent leukemia.