Gemtuzumab Ozogamicin (CMA-676, Mylotarg) for the treatment of CD33+ acute myeloid leukemia

Gemtuzumab Ozogamicin (GO, CMA-676) is a monoclonal antibody against the cellular surface antigen CD33 conjugated with the cytotoxic antibiotic calicheamicin. In the beginning of 2000 it obtained US Food and Drug Administration approval for the treatment of refractory acute myeloid leukemia (AML) expressing CD33 in patients older than 60 years who are not candidates for other chemotherapy. After ligation with the CD33 on the cell surface, GO is internalized and hydrolyzed. Its two components are released into the cytoplasm and calicheamicin enters the nucleus where it associates with the DNA, causing double helix breaks and finally cell death. GO is in general well tolerated. The most frequent adverse effect observed is myelotoxicity, with prolonged neutropenia and thrombocytopenia. Veno-occlusive disease of the liver is a less frequent but severe adverse effect. A phase II study points towards a percentage of overall hematologic response around 30% in the setting of refractory or relapsed disease. Future phase III trials will show the most suitable place of GO in the treatment of AML.     

Monoclonal antibodies in the treatment of cancer, Part 1.

Monoclonal antibodies used in the treatment of cancer are discussed. Monoclonal antibodies are a new class of agents targeted at specific receptors on cancer cells. In addition to having direct cellular effects, antibodies can carry substances, such as radioactive isotopes, toxins, and antineoplastic agents, to the targeted cells. Five monoclonal antibodies--rituximab, trastuzumab, gemtuzumab ozogamicin, alemtuzumab, and ibritumomab tiuxetan--are available for clinical use. Rituximab is active against indolent lymphomas, providing a valuable alternative for patients with relapsed or refractory disease. Rituximab plus cyclophosphamide-doxorubicin-vincristine-prednisone (CHOP) increased survival over CHOP alone in patients with high-grade lymphomas. Trastuzumab has significant activity against HER-2-positive breast cancer, especially in combination with paclitaxel or an anthracycline and cyclophosphamide. Gemtuzumab ozogamicin is an active second-line therapy in older patients with acute myelogenous leukemia, but its role in combination regimens is unclear. Alemtuzumab is a valuable option for salvage therapy of patients with chronic lymphocytic leukemia. Ibritumomab tiuxetan delivers radioactive isotopes to tumor cells and is active against indolent lymphomas in patients who have relapsed after chemotherapy or rituximab therapy. The most common adverse effects of monoclonal antibodies are myelosuppression, infusion-related reactions, and hypersensitivity reactions. Rituximab may cause tumor lysis syndrome, arrhythmias, and pulmonary dysfunction. Alemtuzumab causes immunosuppression, increasing the risk of infection. Gemtuzumab ozogamicin may cause hepatotoxicity, and trastuzumab may cause significant pulmonary or cardiac toxicity. Investigational monoclonal antibodies include edrecolomab and tositumomab. Monoclonal antibodies have a significant role in the management of patients with advanced refractory or relapsed lymphomas and leukemias.     

Monoclonal antibodies in the treatment of cancer, Part 2.

Monoclonal antibodies used in the treatment of cancer are discussed. Monoclonal antibodies are a new class of agents targeted at specific receptors on cancer cells. In addition to having direct cellular effects, antibodies can carry substances, such as radioactive isotopes, toxins, and antineoplastic agents, to the targeted cells. Five monoclonal antibodies--rituximab, trastuzumab, gemtuzumab ozogamicin, alemtuzumab, and ibritumomab tiuxetan--are available for clinical use. Rituximab is active against indolent lymphomas, providing a valuable alternative for patients with relapsed or refractory disease. Rituximab plus cyclophosphamide-doxorubicin-vincristine-prednisone (CHOP) increased survival over CHOP alone in patients with high-grade lymphomas. Trastuzumab has significant activity against HER-2-positive breast cancer, especially in combination with paclitaxel or an anthracycline and cyclophosphamide. Gemtuzumab ozogamicin is an active second-line therapy in older patients with acute myelogenous leukemia, but its role in combination regimens is unclear. Alemtuzumab is a valuable option for salvage therapy of patients with chronic lymphocytic leukemia. Ibritumomab tiuxetan delivers radioactive isotopes to tumor cells and is active against indolent lymphomas in patients who have relapsed after chemotherapy or rituximab therapy. The most common adverse effects of monoclonal antibodies are myelosuppression, infusion-related reactions, and hypersensitivity reactions. Rituximab may cause tumor lysis syndrome, arrhythmias, and pulmonary dysfunction. Alemtuzumab causes immunosuppression, increasing the risk of infection. Gemtuzumab ozogamicin may cause hepatotoxicity, and trastuzumab may cause significant pulmonary or cardiac toxicity. Investigational monoclonal antibodies include edrecolomab and tositumomab. Monoclonal antibodies have a significant role in the management of patients with advanced refractory or relapsed lymphomas and leukemias.     

Monoclonal antibodies for the treatment of acute myeloid leukemia

Currently, patients with acute myeloid leukemia (AML) are treated with cytotoxic chemotherapy and hematopoietic stem cell transplantation (HSCT). With this approach, the majority of patients still die of their disease because of both treatment-related mortality and relapse. Recently, monoclonal antibodies and immunoconjugates have been developed which potentially may increase the efficacy of treatment and decrease morbidity and mortality by specifically targeting the malignant cell. Unconjugated monoclonal antibodies have shown only moderate activity. A second, more effective, approach involves antibody conjugation with radioactive particles or chemotherapeutic agents, such as, immunotoxins, targeted delivery of cell killing. The antigens CD33, CD45, and CD66, are three antigens to which monoclonal antibodies have been directed. Most experience has been with gemtuzumab ozogamicin (Mylotarg) which is an immunoconjugate of an anti-CD33 antibody chemically linked to a potent cytotoxic agent, calicheamicin. Gemtuzumab ozogamicin appears to be particularly active in patients with acute promyelocytic leukemia, possibly related to the high expression of the CD33 antigen on the cell surface. Although gemtuzumab ozogamicin has activity as a single agent, the most promising result may be seen when this agent is combined with conventional cytotoxic chemotherapy. Preliminary studies have suggested a high complete remission rate and randomized clinical trials are underway. A unique potential toxicity has been identified, namely venoocclusive disease or sinusoidal obstructive syndrome which may be problematic among patients who subsequently undergo HSCT. An additional strategy includes radiolabeled monoclonal antibodies to intensify the conditioning regimen prior to HSCT. The most promising results have been obtained with radiolabeled anti-CD45 antibodies.     

Gemtuzumab ozogamicin for the treatment of acute myeloid leukemia

Introduction: Gemtuzumab ozogamicin (GO) is an antibody-drug conjugate consisting of a monoclonal antibody targeting CD33 linked to a cytotoxic derivative of calicheamicin. Despite the known clinical efficacy in relapsed/refractory acute myeloid leukemia (AML), GO was withdrawn from the market in 2010 due to increased early deaths witnessed in newly diagnosed AML patients receiving GO + intensive chemotherapy. In 2017, new data on the clinical efficacy and safety of GO administered on a fractionated-dosing schedule led to re-approval for newly diagnosed and relapsed/refractory AML.

Areas covered: Addition of fractionated GO to chemotherapy significantly improved event-free survival of newly diagnosed AML patients with favorable and intermediate cytogenetic-risk disease. GO monotherapy also prolonged survival in newly diagnosed unfit patients and relapse-free survival in relapsed/refractory AML. This new dosing schedule was associated with decreased incidence of hepatotoxicity, veno-occlusive disease, and early mortality.

Expert commentary: GO represents the first drug-antibody conjugate approved (twice) in the United States for AML. Its re-emergence adds a valuable agent back into the armamentarium for AML. The approval of GO as well as three other agents for AML in 2017 highlights the need for rapid cytogenetic and molecular characterization of AML and incorporation into new treatment algorithms.     

A new sensitive enzyme-linked immunosorbent assay (ELISA) for Alemtuzumab determination: development, validation and application

Alemtuzumab is a humanized (IgG(1)) rat monoclonal antibody to CD52 antigen and is currently used in the treatment of chronic lymphocytic leukemia (CLL) and other CD52-positive lymphoproliferative disorders. Various techniques have been developed to measure Alemtuzumab levels in human serum/plasma. The authors report on the validation of a very sensitive enzyme-linked immunosorbent assay (ELISA) to measure serum concentrations of the humanized IgG(1) using a rabbit polyclonal antibody specifically produced against the rat sequence of Alemtuzumab after papain digestion. The assay was successfully applied to test the serum samples of patients with B-lymphocyte CLL who received Alemtuzumab subcutaneously. This ELISA assay could be easily used to determine human serum levels of Alemtuzumab pre- and post-treatment to optimize dosing and scheduling and to study the relationship between dose and clinical response.     

Gemtuzumab ozogamicin and targeted cancer therapy

Recently, anti-cancer antibodies have been launched in Japan and also immunoconjugates with a cytotoxic compound or a radioisotope have been launched in the USA. Gemtuzumab ozogamicin is a conjugate of anti-CD33 antibody and a cytotoxic calicheamicin derivative. After binding the CD33-positive leukemia cells, gemtuzumab ozogamicin is internalized and releases the calicheamicin derivative. The calichemicin derivative breaks DNA and kills the cells. Gemtuzumab ozogamicin was effective and well tolerated in clinical trials in patients with acute myeloid leukemia (AML) in relapse. It was approved in 2000 by the FDA, and Wyeth K.K. has submitted it as an anti-tumor drug for CD33 positive AML. Two kinds of immunoconjugates, anti-CD20 antibodies with radioisotopes, recently have been launched in the USA for CD20-positive non-Hodgkin's lymphoma. These conjugates showed efficacy in patients who are refractory to the conventional chemotherapies. Targeted therapy with the immunoconjugate that can deliver cytotoxic compounds to specific cells is promising for use in oncology.     

FLT3 Antibody‐based therapy for leukemia

Technological advances in antibody generation and production have facilitated recent clinical and commercial success with antibody‐based cancer therapeutics. The class III receptor tyrosine kinase FLT3 is highly expressed on the blast cells in most cases of acute myelogenous leukemia (AML) and B‐cell acute lymphoblastic leukemia (ALL). Activating mutations of FLT3 are detected in approximately 37% AML patients. FLT3 expression in normal tissue is limited to myeloid and B‐cell precursor cells. Therefore, over‐expressed or mutated FLT3 is an attractive target for therapeutic intervention using monoclonal antibodies. This review will discuss recent progress in the development of anti‐FLT3 antibodies as well as their therapeutic potentials in the treatment of AML and other hematological malignancies. Drug Dev. Res. 67:495–500, 2006. © 2006 Wiley‐Liss, Inc.     

Inotuzumab ozogamicin in the treatment of B-cell acute lymphoblastic leukemia

INTRODUCTION: Inotuzumab ozogamicin (CMC-544) is a humanized anti-CD22 monoclonal antibody conjugated with calicheamicin. Preclinical data indicate activity against B-cell tumors and early results from clinical trials indicate activity against B-cell lineage acute lymphoblastic leukemia (ALL). AREAS COVERED: This paper reviews the design, pharmacokinetic and pharmacodynamic characteristics, and preclinical and clinical experience of inotuzumab ozogamicin in adult ALL. EXPERT OPINION: Inotuzumab ozogamicin appears as an effective salvage therapy in patients with advanced ALL, allowing more patients to receive stem cell transplant (SCT) with encouraging response rates. This agent should provide a unique opportunity to treat selected ALL patient subpopulations.     

Monoclonal Antibodies as Diagnostics; an Appraisal

Ever since the development of Hybridoma Technology in 1975 by Kohler and Milstein, our vision for antibodies as tools for research for prevention, detection and treatment of diseases, vaccine production, antigenic characterization of pathogens and in the study of genetic regulation of immune responses and disease susceptibility has been revolutionized. The monoclonal antibodies being directed against single epitopes are homogeneous, highly specific and can be produced in unlimited quantities. In animal disease diagnosis, they are very useful for identification and antigenic characterization of pathogens. Monoclonal antibodies have tremendous applications in the field of diagnostics, therapeutics and targeted drug delivery systems, not only for infectious diseases caused by bacteria, viruses and protozoa but also for cancer, metabolic and hormonal disorders. They are also used in the diagnosis of lymphoid and myeloid malignancies, tissue typing, enzyme linked immunosorbent assay, radio immunoassay, serotyping of microorganisms, immunological intervention with passive antibody, antiidiotype inhibition, or magic bullet therapy with cytotoxic agents coupled with anti mouse specific antibody. Recombinant deoxyribonucleic acid technology through genetic engineering has successfully led to the possibility of reconstruction of monoclonal antibodies viz. chimeric antibodies, humanized antibodies and complementarily determining region grafted antibodies and their enormous therapeutic use.     

Evolving role of monoclonal antibodies in the treatment of chronic lymphocytic leukemia

Recognition of cancer-specific antigens resulted in development of monoclonal antibodies as treatments for various neoplasms including chronic lymphocytic leukemia (CLL). Two monoclonal antibodies, alemtuzumab and rituximab, have been extensively studied, as monotherapy or in combination, in patients with various clinical stages of CLL. Alemtuzumab, particularly when combined with fludarabine-based chemotherapy, sequentially or concomitantly, represents a promising therapeutic approach that results in improved efficacy by further reducing levels of residual disease in previously untreated or relapsed/refractory CLL. On the other hand, single-agent rituximab has limited activity by itself, even at very high doses, and seldom induces complete remissions. However, rituximab is feasible to combine with conventional chemotherapies such as purine analogs, alkylating chemotherapy and/or alemtuzumab. Newer monoclonal antibodies are already showing activity in relapsed/refractory CLL and will eventually be evaluated in combinations with conventional chemotherapy, or with already established antibodies. Modern definitions for assessment of responses such as minimal residual disease negativity (MRD negativity) are emerging and, consequently, development of assays capable of measuring such responses. MRD negativity should become the primary objective of clinical trials when evaluating treatment interventions in patients with CLL. The future of monoclonal antibodies for treatment of CLL is bright.     

The role of CD33 as therapeutic target in acute myeloid leukemia

CD33 is a myeloid differentiation antigen that is displayed on acute myeloid leukemia (AML) blasts in most patients and, possibly, leukemic stem cells in some, and has thus served as target for antibody-based therapies for many years. Validation for this approach comes from the antibody–drug conjugate, gemtuzumab ozogamicin, which improves survival of some patients with AML when added to induction chemotherapy. Still, CD33 is a challenging target because of its low expression and slow internalization; these characteristics limit antibody-dependent cell-mediated cytotoxicity and intracellular drug accumulation and, consequently, the activity of unlabeled and toxin-carrying antibodies. Very promising preclinical data are now available from an improved antibody–drug conjugate and CD33-targeted strategies that redirect immune effector cells to eradicate the leukemia, most notably bispecific antibodies and chimeric antigen receptor T-cell immunotherapy. In parallel to their clinical testing, efforts will be needed to identify the patients that most likely benefit from such agents and the disease stage in which they are most efficacious. With enhanced activity of CD33-directed therapies, toxic effects on normal hematopoiesis will increase and require excellent supportive care measures, or even rescue with donor cells, to minimize morbidity and mortality from expected cytopenias and to optimize treatment outcomes with these therapeutics.     

Mechanism of action of rituximab

Rituximab, the humanized chimeric anti-CD20 monoclonal antibody, represents a powerful tool for treating B-cell malignancies and is licensed for the treatment of relapsed or chemorefractory low-grade or follicular non-Hodgkin's lymphoma (NHL). It has a unique mode of action and can induce killing of CD20+ cells via multiple mechanisms. The direct effects of rituximab include complement-mediated cytotoxicity and antibody-dependent cell-mediated cytotoxicity, and the indirect effects include structural changes, apoptosis, and sensitization of cancer cells to chemotherapy. In vitro studies have made a significant contribution to the understanding of these mechanisms of action and have led to the development of innovative and effective treatment strategies to optimize patient response. The most significant of these strategies is the combination of rituximab and CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine and prednisone), which is proving a highly effective combination in the treatment of NHL. However, all patients do not respond equally well to rituximab, and in vitro studies have identified a possible mechanism of resistance involving the anti-complement inhibitors CD55 and CD59. Neutralizing antibodies to CD55 and CD59 can overcome resistance to rituximab-mediated complement-mediated cytotoxicity in vitro. This paper overviews our understanding of the mechanisms of action of rituximab and identifies how this knowledge could be applied in a clinical setting to maximize response in both sensitive and resistant patients.     

Anti-CD123 antibody-modified niosomes for targeted delivery of daunorubicin against acute myeloid leukemia

A novel niosomal delivery system was designed and investigated for the targeted delivery of daunorubicin (DNR) against acute myeloid leukemia (AML). Anti-CD123 antibodies conjugated to Mal-PEG₂₀₀₀-DSPE were incorporated into normal niosomes (NS) via a post insertion method to afford antibody-modified niosomes (CD123-NS). Next, NS was modified with varying densities of antibody (0.5 or 2%, antibody/Span 80, molar ratio), thus providing L-CD123-NS and H-CD123-NS. We studied the effect of antibody density on the uptake efficiency of niosomes in NB4 and THP-1 cells, on which CD123 express differently. Our results demonstrate CD123-NS showed significantly higher uptake efficiency than NS in AML cells, and the uptake efficiency of CD123-NS has been ligand density-dependent. Also, AML cells preincubated with anti-CD123 antibody showed significantly reduced cellular uptake of CD123-NS compared to control. Further study on the uptake mechanism confirmed a receptor-mediated endocytic process. Daunorubicin (DNR)-loaded H-CD123-NS demonstrated a 2.45- and 3.22-fold higher cytotoxicity, compared to DNR-loaded NS in NB4 and THP-1 cells, respectively. Prolonged survival time were observed in leukemic mice treated with DNR-H-CD123-NS. Collectively, these findings support that the CD123-NS represent a promising delivery system for the treatment of AML.     

Gemtuzumab ozogamicin: a review of its use in acute myeloid leukaemia

Gemtuzumab ozogamicin (Mylotarg) is a conjugate of a monoclonal antibody and calicheamicin, which targets the membrane antigen CD33 in CD33-positive acute myeloid leukaemia (AML) and, after cell internalisation, releases a derivative of the cytotoxic calicheamicin component. In the US, it is approved as monotherapy in patients aged > or =60 years with a first relapse of AML who are ineligible for other cytotoxic therapy. Monotherapy with gemtuzumab ozogamicin results in complete remission (CR) or CR with incomplete platelet recovery (CRp) in approximately =25% of adults (including those aged > or =60 years) with CD33-positive AML in first relapse. Preliminary data indicate a potential role for gemtuzumab ozogamicin as a component of induction or consolidation regimens in adults and, based on an early study, in the treatment of children with AML, although randomised, controlled studies are needed. Serious adverse events, notably hepatotoxicity, characterise its tolerability profile, but gemtuzumab ozogamicin is comparatively well tolerated by most patients. Gemtuzumab ozogamicin is a valuable new treatment option for patients aged > or =60 years with CD33-positive AML in first relapse for whom other cytotoxic chemotherapy is not considered appropriate; patients with a first CR (CR1) of >12 months are likely to have the best outcome.     

Novel monoclonal antibodies for the treatment of chronic lymphocytic leukemia

For many years, alkylating agents and purine nucleoside analogs (PNA) have been considered the drug of choice for treatment of chronic lymphocytic leukemia (CLL). More recently the introduction of monoclonal antibodies (mAb), especially rituximab directed against CD20 and alemtuzumab directed against CD52, has renewed interest in CLL therapy. Over the last few years, several new mAbs directed against lymphoid cells have been developed and investigated in preclinical studies and clinical trials. Some of them are highly active in CLL. New mAbs directed against CD20 include human mAb ofatumumab (HuMax CD20), IMMU-106 (hA20) which has a >90% humanized framework and GA-101, a novel third - generation fully humanized and optimized mAb. These agents are highly cytotoxic against B-cell lymphoid cells and are evaluated in CLL. Lumiliximab (anti-CD23 mAb) is a genetically engineered macaque-human immunoglobulin (Ig) A1. This antibody showed high activity and good tolerability in phase I clinical trial and is evaluated in phase I/II clinical trials as a single agent and in combination. Epratuzumab is a humanized anti-CD22 mAb currently used in clinical trials for treatment of non-Hodgkin lymphoma and autoimmune disorders. Further studies are needed to elucidate the role of this agent in CLL. Apolizumab (HU1D10) is a humanized IgG1 antibody specific for a polymorphic determinant found on the HLA-DRbeta chain. Preclinical and early clinical studies suggest that this mAb has some activity in CLL. HCD122 (CHIR-12.12) and SGN-40 are anti-CD40 mAbs which induce cytotoxicity against CLL cells. Phase I study has shown a favorable safety profile and some activity of HCD122 in pretreated CLL patients. Immunotoxins, especially BL22, LMP-2 and denileukin diftitox, are also being evaluated in lymphoid malignancies and seem to be active in CLL. Finally, antiangiogenic mAbs, especially bevacimzumab, have a potential therapeutic role in this disease. In this review, new mAbs, potentially useful in CLL are presented.     

Evolving role of monoclonal antibodies in the treatment of chronic lymphocytic leukemia

Recognition of cancer-specific antigens resulted in development of monoclonal antibodies as treatments for various neoplasms including chronic lymphocytic leukemia (CLL). Two monoclonal antibodies, alemtuzumab and rituximab, have been extensively studied, as monotherapy or in combination, in patients with various clinical stages of CLL. Alemtuzumab, particularly when combined with fludarabine-based chemotherapy, sequentially or concomitantly, represents a promising therapeutic approach that results in improved efficacy by further reducing levels of residual disease in previously untreated or relapsed/refractory CLL. On the other hand, single-agent rituximab has limited activity by itself, even at very high doses, and seldom induces complete remissions. However, rituximab is feasible to combine with conventional chemotherapies such as purine analogs, alkylating chemotherapy and/or alemtuzumab. Newer monoclonal antibodies are already showing activity in relapsed/refractory CLL and will eventually be evaluated in combinations with conventional chemotherapy, or with already established antibodies. Modern definitions for assessment of responses such as minimal residual disease negativity (MRD negativity) are emerging and, consequently, development of assays capable of measuring such responses. MRD negativity should become the primary objective of clinical trials when evaluating treatment interventions in patients with CLL. The future of monoclonal antibodies for treatment of CLL is bright.     

急性白血病免疫表型与预后的关系

目的探讨急性白血病（AL）免疫表型与预后的关系。方法采用流式细胞技术（FCM）对75例AL患者进行免疫表型分析,并评价不同的免疫表型对预后的影响。结果（1）82％的急性髓性白血病（AML）患者表达CD15、CD33、CD44、CD117,88％的急性淋巴细胞性白血病（ALL）患者表达CD2、CD3、CD7、CD19、CD20,伴淋系抗原表达的AML（Ly＋AML）占13％,伴髓系抗原表达的ALL（My＋ALL）占11％。（2）按免疫表型的表达特征,在AML和ALL中以系列专一表达所占的比例最高,且临床治疗预后较好。裸细胞型表达在AML和ALL中所占的比例最少,且临床治疗预后极差。杂合表达的病例中,CD7^＋的AML患者的完全缓解率（CR）明显低于系列专一表达者,预后极差。结论AL免疫表型可出现系列专一表达、杂合表达及裸细胞型表达三种类型。杂合表达和裸细胞型表达的患者CR率低于系列专一表达者,临床预后不好。     

86例成人急性髓性白血病免疫表型分析

常规使用10种单抗，用流式细胞仪（FACS）或荧光显微镜（FM）间接免疫荧光标记法检测了86树成人急性髓性白血病（AML）患者骨髓细胞的免疫标志。结果显示，髓系标志中CD33、CD13诊断价值较高，而CD15、CD14阳性率低。31．4％AML有淋系抗原表达，无单抗标记AML占16．3％，47．6％的患者表达CD34.FACS检测较FM更敏感、特异。     

Immunotherapeutic and immunoregulatory drugs in haematologic malignancies

A better understanding of the biology and pathogenesis of hematological malignancies has led to the development of immunotherapeutic and immunoregulatory drugs. Many of these agents have revolutionized the current treatment modalities, while others are under investigation. Rituximab (anti-CD20 antibody) has been established as the gold standard of treatment for aggressive B-cell lymphomas in combination with CHOP and has shown significant activity as monotherapy in the treatment of indolent B-cell lymphomas. In follicular lymphomas the combination of Rituximab with chemotherapy improves the outcome compared to chemotherapy alone. CD 20-based radioimmunotherapy, with the advantage of the bystander effect, represents an additional therapeutic alternative in B-cell lymphomas and may produce tumor regression in Rituximab resistant patients. The anti-CD52 monoclonal antibody, alemtuzumab, further expands the armamentarium against lymphoid malignancies producing high response rates in these entities. Antibody-targeted chemotherapy such as gemtuzumab ozogamicin, consisting of an anti-CD33 antibody combined to calicheamicin, has shown efficacy in the treatment of refractory acute myeloid leukemia; exact indications, timing and dosing schedule for optimized efficacy remain to be determined. Interferons have proven significant activity in cutaneous lymphomas, hairy cell leukemia and chronic myelogenous leukemia by mechanisms that are not fully elucidated. Thalidomide, by acting as an immunomodulatory and antiangiogenic agent can modulate neoplastic cells microenvironment and lead to disease control in multiple myeloma as well as in numerous other hematological malignancies. Bortezomib, a proteasome inhibitor, displays significant anti-tumor activity, especially in multiple myeloma and lymphoproliferative disorders. The addition of these agents in therapeutic regimens has improved considerably the treatment of hematological malignancies.