Advertisement
CCR Focus

Antibody-Drug Conjugates of Calicheamicin Derivative: Gemtuzumab Ozogamicin and Inotuzumab Ozogamicin

Alejandro D. Ricart
DOI: 10.1158/1078-0432.CCR-11-0486 Published October 2011

Abstract

Antibody-drug conjugates (ADC) are an attractive approach for the treatment of acute myeloid leukemia and non-Hodgkin lymphomas, which in most cases, are inherently sensitive to cytotoxic agents. CD33 and CD22 are specific markers of myeloid leukemias and B-cell malignancies, respectively. These endocytic receptors are ideal for an ADC strategy because they can effectively carry the cytotoxic payload into the cell. Gemtuzumab ozogamicin (GO, Mylotarg) and inotuzumab ozogamicin consist of a derivative of calicheamicin (a potent DNA-binding cytotoxic antibiotic) linked to a humanized monoclonal IgG4 antibody directed against CD33 or CD22, respectively. Both of these ADCs have a target-mediated pharmacokinetic disposition. GO was the first drug to prove the ADC concept in the clinic, specifically in phase II studies that included substantial proportions of older patients with relapsed acute myeloid leukemia. In contrast, in phase III studies, it has thus far failed to show clinical benefit in first-line treatment in combination with standard chemotherapy. Inotuzumab ozogamicin has shown remarkable clinical activity in relapsed/refractory B-cell non-Hodgkin lymphoma, and it has started phase III evaluation. The safety profile of these ADCs includes reversible myelosuppression (especially neutropenia and thrombocytopenia), elevated hepatic transaminases, and hyperbilirubinemia. There have been postmarketing reports of hepatotoxicity, especially veno-occlusive disease, associated with GO. The incidence is ∼2%, but patients who undergo hematopoietic stem cell transplantation have an increased risk. As we steadily move toward the goal of personalized medicine, these kinds of agents will provide a unique opportunity to treat selected patient subpopulations based on the expression of their specific tumor targets. Clin Cancer Res; 17(20); 6417–27. ©2011 AACR.

Introduction

It is surprising that few monoclonal antibodies (mAb) have been approved for the treatment of acute myeloid leukemia (AML) and non-Hodgkin lymphoma (NHL) since the first approval of rituximab in 1997. These malignancies localize in areas that are readily accessible to circulating mAbs, such as the circulating blood, lymph nodes, and bone marrow. The disposition of intact mAbs is also favorable for their treatment: Distribution into other tissues is slow, and volumes of distribution are generally low (1). Antibody-drug conjugates (ADC) are an attractive approach for the treatment of these diseases, which in most cases are inherently sensitive to cytotoxic agents. This CCR Focus section describes a significant number of ADCs currently in clinical development (2–7).

The sialic-acid–binding immunoglobulin-like lectins (siglecs) include a family of receptors that are restrictedly expressed on one or a few immune cell types, making them attractive for targeted therapy (8, 9). CD33 (also known as siglec-3) and CD22 (siglec-2) were identified as markers of myeloid leukemias and B-cell lymphomas, respectively, almost 25 years ago. Siglecs are endocytic receptors and thus ideal for an ADC strategy because they can effectively carry the complex with its cytotoxic payload into the cell (8). This is a striking difference from other antibody targets, such as CD20, for which human cells are highly heterogeneous in their internalization ability (10).

Gemtuzumab Ozogamicin

Description

Gemtuzumab ozogamicin (GO, Mylotarg; Fig. 1) consists of a semisynthetic derivative of calicheamicin (N-acetyl-γ calicheamicin 1,2-dimethyl hydrazine dichloride), a potent enediyne DNA-binding cytotoxic antibiotic, linked to an engineered humanized monoclonal IgG4 antibody (hP67.6) directed against the CD33 antigen present on leukemic myeloblasts in most patients with AML (∼80%). IgG4 has interesting properties for a carrier. It has the longest circulating half-life of all isotypes, with limited ability for complement fixation and antibody-dependent cellular toxicity. The unconjugated antibody hP67.6 is not known to be cytotoxic per se (11). Calicheamicin was isolated from the actinomycete Micromonospora echinospora calichensis (12). The cytotoxic drug is attached to the antibody through a covalent linkage (condensation) of a bifunctional linker, 4-(4-acetylphenoxy)butanoic acid (AcBut linker), which allows stability in physiologic buffers (pH 7.4) and efficient calicheamicin release inside lysosomes (pH ∼4; ref. 11). The average loading of calicheamicin on the antibody is 2.5 mol/mol (drug-loading range of 2–3 mol of calicheamicin per mole of antibody; ref. 11). Calicheamicin binds to the minor groove in the DNA and causes double-strand DNA breaks, resulting in cell death (please refer to Fig. 1 to follow this sequence; ref. 12). The custom-made, well-controlled, hydrolysable bond with the AcBut linker showed significantly more potent and selective calicheamicin conjugates of P67.6 against HL-60 cells in vitro. This effective intracellular hydrolytic release of the calicheamicin derivative was important for its intracellular trafficking and the subsequent access to its DNA target. This indicates the importance of designing linkers that are specific for the individual target cell type (11).

Figure 1.
Figure 1.

A, immunoconjugate binding and internalization. B, immunoconjugate intracellular trafficking from endosome to lysosome, with linker cleavage. Acid-labile AcBut hydrazone linker is cleaved in the acid environment of lysosome. C, calicheamicin derivative is released intracellularly. The reduction to the active enediyne form requires glutathione. D, the active enediyne form binds to the minor groove in DNA and causes double-strand breaks, resulting in cell death. E, Pgp-mediated efflux may be a mechanism of drug resistance in leukemic cells. The immunoconjugate structure on the upper right is modified from Advani et al. (52). Reprinted with permission. © 2008 American Society of Clinical Oncology.

Pharmacodynamics

Saturation and internalization were analyzed in a phase II study (13). Within 3 to 6 hours after a 9 mg/m2 infusion of GO, nearly complete saturation of CD33 antigens was reached for leukemic and normal myeloid cells in blood. Although the mean maximal binding of GO to myeloid blast cells was comparable to monocytes, the maximal binding to granulocytes was significantly lower, with no binding to lymphocytes. These data are in accordance with the known expression levels of the CD33 antigen on these cells. On the other hand, this target is not (considerably) expressed on normal CD34+ pluripotent hematopoietic stem cells or on nonhematopoietic tissues (see “Safety” section for gemtuzumab ozogamicin below; ref. 14). Saturation levels before the second infusion were increased compared with baseline levels (before the first infusion) in that phase II study, apparently due to remaining GO from the first infusion. Upon binding to CD33, GO was rapidly internalized, as determined by the decrease in maximal membrane binding (13). In vitro studies using pulse labeling with GO showed a continuous renewal of CD33, which could increase the internalization and thereby the intracellular accumulation of the cytotoxic agent (13). Using a lentivirus-mediated gene transfer to manipulate CD33 expression in cell lines that normally lack CD33 or have very low levels of CD33, Walter and colleagues (15) showed a quantitative relationship between CD33 expression and GO-induced cytotoxicity. The CD33 cytoplasmic immunoreceptor tyrosine-based inhibitory motifs controlled the internalization process, and point mutations that disrupted these motifs not only prevented effective internalization but also significantly reduced GO-induced cytotoxicity. However, preliminary multivariate analyses showed that CD33 expression levels were not correlated with clinical response or overall survival (13, 16). This observation raises the possibility that the effects of GO in the clinic might be influenced by other features, such as cytokinetics, cytogenetics, multidrug resistance (MDR), and other prognostic factors. It is well known that AML is a heterogeneous disease with a complex biology (17). Cytotoxicity by clinically relevant GO concentrations is partially mediated by CD33 expression, and efficient GO uptake can also occur via non-CD33–mediated endocytosis. GO-mediated death of human CD33-negative leukemic lymphoblasts was shown both in vitro and in vivo in a NOD/SCID mouse model (18). Moreover, sensitivity to GO was at least partially determined by the activation status of leukemic cells, with the cells in activated phases of the cell cycle being most effective in CD33-specific internalization, renewed expression of CD33, and non-CD33–mediated GO uptake via endocytosis (18). The impossibility of quantitating CD33 expression per cell in the multicenter clinical setting may also contribute to the lack of correlation. CD33 expression classified as positive (>20% of blasts positive) versus negative (<20% of blasts positive) was not predictive, and there was no relationship with the degree of blast positivity in the AML15 trial (the largest GO randomized phase III study; ref. 17). Because cytotoxicity is dependent on the calicheamicin component, tumor cells exhibiting P-glycoprotein (Pgp)-mediated MDR may be able to escape the effect of GO. This is suggested by the correlation between clinical response and low Pgp activity, or low levels of dye efflux by leukemic blast cells (16, 19, 20). In addition, in vitro drug-induced apoptosis could be increased by Pgp antagonists (e.g., cyclosporine; ref. 20).

Pharmacokinetics

The pharmacokinetics of GO were characterized in patients with AML (21). The recommended phase II dose (RP2D) was determined to be 9 mg/m2 infused i.v. over 2 hours, repeated on day 14 (16). Increased serum concentrations were observed after the second dose and were believed to be due to a decrease in clearance by CD33-positive blast cells, a result of the lower peripheral leukemic burden after the first dose (21, 22). The concentration profiles of calicheamicin derivative followed the same time course as hP67.6, evidence that the payload remained conjugated to the antibody and was delivered to the leukemic cells. No relationship was found between plasma concentration and response at the RP2D (21). Despite high interpatient variability, the pharmacokinetic parameters of the components (hP67.6, total and unconjugated calicheamicin derivative) were not different based on gender or age, including a comparison between pediatric patients and adults (22, 23). Weight and body surface area did not affect the pharmacokinetics of GO (23). Although most mAbs in oncology are administered on the basis of body weight or surface area, the issue of how to dose an antibody like GO, with a significant target-mediated disposition, is still controversial.

Safety

In phase I studies, the major toxicity of GO was reversible myelosuppression, especially neutropenia and thrombocytopenia, which was thought to result from the expression of CD33 on myeloid progenitor cells (24). Although patients treated with GO in phase II studies had relatively high incidences of myelosuppression, grade 3 or 4 hyperbilirubinemia (23%), and elevated hepatic transaminase levels (17%), the incidences of severe mucositis (4%), severe nausea and vomiting (11%), and infections (28%) were relatively low. No treatment-related cardiotoxicity, cerebellar toxicity, or alopecia was observed (16). Infusion-related symptoms were usually transient and occasionally required hospitalization. GO was easy to administer compared with conventional chemotherapy regimens for relapsed AML. A significant proportion of patients received GO on an outpatient basis (38% and 41% for the first and second doses, respectively), and the median duration in hospital was 24 days (16). Postmarketing reports of fatal anaphylaxis, adult respiratory distress syndrome (ARDS), and hepatotoxicity [especially veno-occlusive disease (VOD), also referred to as sinusoidal obstruction syndrome], with and without associated hematopoietic stem cell transplantation (HSCT), required labeling revisions and the initiation of a registration surveillance program. Patients on GO treatment need to be monitored for delayed hepatotoxicity, hypoxia, and infusion reactions (25). Hepatotoxicity was originally believed to reflect nonspecific hepatocellular endocytosis rather than antigen-mediated effects. However, an alternative hypothesis considers that GO targets CD33-positive cells in hepatic sinusoids (including Kupffer cells; refs. 26 and 27). It is now clear that when administered as a single agent at the recommended dose and schedule, GO has a relatively small association with VOD (1–2%), but patients who undergo HSCT within a short interval after GO administration (≤3.5 months) are at increased risk (28–30). Tumor lysis and ARDS have been reported in patients with leukocytes >30,000/μL, resulting in the recommendation that the leukocyte count be reduced to <30,000/μL prior to GO administration (25). Another potential benefit from reducing the leukemic cell burden prior to GO administration is that high CD-33 antigen loads in blood may consume GO and limit its distribution into bone marrow, which would decrease leukemic cell killing (31).

Clinical efficacy

Progress in the treatment of AML has been less evident in patients 60 years of age or older than it has in younger patients. Standard chemotherapy produces dismal results in the older population, usually with poor tolerance and sometimes with a high incidence of toxic events, including death. A total of 40 patients were treated at 8 dose levels from 0.25 to 9 mg/m2 in the original phase I study of GO. Morphologic evidence of leukemia within the bone marrow (>5% blast cells) was seen in all patients before treatment. After treatment with 1 to 3 doses of GO, 8 of 40 patients (20%) had <5% leukemic blast cells upon morphologic examination of bone marrow aspirate and biopsy specimens (24). Three open-label, multicenter trials were conducted to evaluate the efficacy and safety of single-agent GO. The study population for the initial report from these 3 studies comprised 142 patients with AML in first relapse with a median age of 61 years. Thirty percent of the patients obtained remission as characterized by ≤5% blasts in the marrow, recovery of neutrophils to at least 1,500/μL, and transfusion independence (16). Based on the efficacy and safety data of these pivotal studies, the U.S. Food and Drug Administration granted marketing approval under the accelerated approval regulations in 2000 (25). GO was indicated for the treatment of patients with CD33-positive AML in first relapse who were 60 years of age or older and were not considered candidates for cytotoxic chemotherapy, and later it was also approved in Europe and Japan. The initial publication (and submission; ref. 16) was followed by a final report covering the total of 277 patients enrolled in these 3 studies (29). A number of phase II studies in relapsed, refractory, and untreated AML have been published, including feasibility trials integrating GO with chemotherapy (Tables 1 and 2). In general, the results suggested clinical activity in relapsed AML with an acceptable safety profile, opportunity for first-line therapy, and remarkable activity in relapsed acute promyelocytic leukemia (APL; Tables 1 and 2). This type of AML combines a high and homogeneous expression of CD33 with low levels or absence of Pgp (32–34). GO has shown prolonged molecular remissions in APL, both as a single agent and in combination, without reports of VOD (35–40).

View this table:
Table 1.

Relevant gemtuzumab ozogamicin single-agent studies in adult patients

View this table:
Table 2.

Relevant gemtuzumab ozogamicin studies of combination therapy in adult patients

However, the required post-approval study (SWOG S0106), combining GO with daunorubicin and cytarabine (Ara-C) in first-line AML patients under the age of 61, failed to confirm clinical benefit. This randomized study was stopped early based on interim results showing no evidence of improved rates of complete remission (CR) or survival, with a significantly higher rate of fatal induction toxicity (5.8% in the GO-chemotherapy arm vs. 0.8% in the chemotherapy-alone arm; P = 0.002; ref. 41). The most common fatal adverse events that were at least possibly attributable to treatment were hemorrhage, infection, and ARDS. One death in the GO-chemotherapy arm was attributable to VOD (41). A second phase III study (AML15) evaluated the addition of GO to induction and/or consolidation therapy in the first-line treatment of patients up to 70 years of age with AML. This study also failed to show improvement in clinical benefit in the intent-to-treat population with the addition of GO, but there was no significant additional toxicity. Of note, a subset analysis by cytogenetics showed a highly significant interaction with induction GO (P = 0.001), and a significant survival benefit for patients with favorable cytogenetics (17, 42). The sponsor, Pfizer Inc., voluntarily withdrew the new drug application for GO (Mylotarg) in the United States in October 2010. GO was withdrawn from the U.S. and European markets; however, it continues to be commercially available in Japan, where it has received full regulatory approval. GO is still available for selected investigator-initiated research, including clinical trials in APL.

Inotuzumab Ozogamicin

Description and pharmacodynamics

Inotuzumab ozogamicin (Fig. 1) is an ADC composed of G544, an IgG4 isotype that specifically recognizes human CD22, and the derivative of calicheamicin. The majority (>90%) of NHLs are of B-cell origin, with CD22 being expressed in ∼60% to >90% of B-lymphoid malignancies (43–45). CD22 has many of the ideal properties for an ADC target (Table 3). Unconjugated G544, having no effector function, has no antitumor activity; instead, conjugation with the cytotoxic payload confers potent dose-dependent cytotoxicity in in vitro and in vivo animal tumor models (46–48). Inotuzumab ozogamicin displayed greater single-agent therapeutic benefit than either CVP (cyclophosphamide, vincristine, and prednisone) or CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) in xenograft models, and it induced superior antitumor activity when coadministered with standard chemotherapeutic regimens (49). Nevertheless, as with GO, inotuzumab ozogamicin was not effective in Pgp-positive sublines (Daudi/MDR and Raji/MDR cells), and MDR modifiers (PSC833 and MS209) restored the cytotoxic effect (48). In clinical samples, the cytotoxic effect was inversely related to the amount of Pgp (P = 0.003) and to intracellular rhodamine-123 accumulation (P < 0.001). Conversely, the effect positively correlated with the amount of CD22 (P = 0.010; ref. 48).

View this table:
Table 3.

Characteristics of CD22 that make it a good target for antibody-based therapy

Moreover, inotuzumab ozogamicin was effective against human B-cell lymphomas resistant to rituximab in murine models, and its combination with rituximab showed additive efficacy (50). Downregulation of CD20 and upregulation of complement inhibitory factors play a central role in acquired resistance to rituximab. CD55 is a regulator of complement-dependent cytotoxicity in malignant B cells, and its expression correlates with resistance to complement-dependent cytotoxicity, which is one of the mechanisms of action of rituximab. In Daudi and Raji cells, the effect of rituximab significantly increased within 12 hours after incubation with inotuzumab ozogamicin. The levels of CD22 and CD55 were significantly reduced (P < 0.001), but the CD20 level remained constant or increased for 12 hours. Similar results were obtained in cells from patients. The antiproliferative and apoptotic effects of inotuzumab ozogamicin were greater than those of rituximab (51).

In humans, decreases in mean CD22+ fluorescence intensity by flow cytometry were observed immediately after the first dose of inotuzumab ozogamicin, and its intensity seemed even more attenuated after dose 2 (Fig. 2A; ref. 52). Finally, inotuzumab ozogamicin showed significant activity against CD22+ leukemia, and it is now being evaluated in patients with CD22+ acute lymphoblastic leukemia (53). The relationship between CD22 expression and inotuzumab ozogamicin cytotoxicity has not been fully evaluated yet.

Figure 2.
Figure 2.

Pharmacodynamics, pharmacokinetics, and clinical activity of inotuzumab ozogamicin. A, mean (SD) molecular equivalents of soluble fluorophore expression of CD19+ lymphocytes that are CD22-phycoerythrin–positive before and after the first and second doses. These are derived from lymphocytes exhibiting ≥500 CD19+ events from flow cytometric analysis. B, concentration-time curves of intact ADC (CMC-544) and its components after the first dose of 1.8 mg/m2. C, Kaplan-Meier estimates of progression-free survival according to lymphoma type and sensitivity to previous therapy in the phase I–II study of inotuzumab ozogamicin plus rituximab (rituximab, 375 mg/m2; inotuzumab ozogamicin, 1.8 mg/m2) ITT population. Panels A and B courtesy of Joseph Boni. Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved. Advani et al. (52). Panel C courtesy of Dr. Erik Vandendries.

Pharmacokinetics

The first-in-human study determined the maximum-tolerated dose (MTD), RP2D, and safety profile of inotuzumab ozogamicin in 79 patients with CD22-positive B-cell NHL (52). The MTD was declared to be 1.8 mg/m2. No dose-limiting toxicity occurred at this dose given once every 4 weeks in 6 patients, and thus this regimen was selected for an expansion cohort. Pharmacokinetic samples were available for inotuzumab ozogamicin, G544, and total and free calicheamicin derivatives. The data indicated that drug disposition was nonlinear with dose or number of doses. For the ADC and total calicheamicin derivative, increases in area under the curve extrapolated over dosing interval τ (AUCτ) with dose and increases in AUCτ with period were observed. The increase in AUCτ with period is thought to be secondary to the reduction in target (CD22) after the initial dose. G544 and total calicheamicin derivative exhibited similar trends of elimination, and the free calicheamicin derivative concentration remained below 1 ng/mL over time, suggesting that the linker is considerably stable in plasma (Fig. 2B; ref. 52). The pharmacokinetic profiles of Japanese patients seemed to be similar to those of non-Japanese patients (54). The pharmacokinetic profile of inotuzumab ozogamicin when combined with rituximab also seemed to be similar to that reported for its use as monotherapy (55).

Safety

In the first-in-human study, dose-limiting toxicity consisted of grade 4 thrombocytopenia and grade 4 neutropenia. Common adverse events at the MTD were thrombocytopenia, asthenia, nausea, and neutropenia (52). As a single agent, in patients with indolent relapsed/refractory NHL, the most common treatment-related adverse events were thrombocytopenia (65%), neutropenia (53%), elevated aspartate aminotransferase (48%), leukopenia (40%), nausea (40%), fatigue (35%), lymphopenia (35%), decreased appetite (33%), and elevated alkaline phosphatase (25%). Common grade 3/4 adverse events were all hematologic: thrombocytopenia (48%), neutropenia (28%), and lymphopenia (12.5%; ref. 56). Three of the ∼390 patients who have been exposed to inotuzumab ozogamicin have developed VOD (incidence < 1%; data on file, Pfizer).

Clinical efficacy

Clinical activity was observed in previously treated patients in the first-in-human study, with an objective response rate of 39% [68% in patients with follicular lymphoma (FL) treated at the MTD; ref. 52]. Thus, inotuzumab ozogamicin monotherapy is being further investigated in patients with indolent NHL (56). Preliminary data for 43 patients with CD22+ indolent NHL (including 35 with FL) who had progressed to ≥2 therapies and exhibited refractory disease to anti-CD20 therapy were recently presented. An objective response rate of 53% (19% CR; 66% in FL patients) was observed (56). Potential clinical and molecular determinants of response to inotuzumab ozogamicin are being evaluated in phase II studies.

The combination of inotuzumab ozogamicin plus rituximab was evaluated in phase I–II studies, and investigators obtained encouraging evidence of clinical activity and a safety profile similar to that previously reported for inotuzumab ozogamicin as a single agent, with hematologic adverse events being the most frequent toxicities. During the dose-escalation phase, the MTD was 375 mg/m2 of rituximab on day 1, followed by 1.8 mg/m2 of inotuzumab ozogamicin on day 2, repeated once every 4 weeks (57). With this schedule, the preliminary objective response rate is 84% (median progression-free survival not reached) in patients with relapsed FL (n = 38; 1–2 prior therapies) and 80% in patients with relapsed diffuse large B-cell lymphoma with a median progression-free survival of 15.1 months (n = 40; 1–2 prior therapies; ref. 55). Response to previous therapy seems to be a major prognostic factor: The objective response rate was just 18% in patients with rituximab-refractory disease, with a median progression-free survival of only 1.7 months (Fig. 2C; ref. 55). Table 4 presents a summary of the clinical studies on inotuzumab ozogamicin conducted to date. A randomized, open-label, phase III trial is currently evaluating rituximab plus inotuzumab ozogamicin versus a defined investigator's choice of rituximab plus bendamustine or rituximab plus gemcitabine in patients with relapsed/refractory aggressive B-cell NHLs who are not candidates for high-dose chemotherapy.

View this table:
Table 4.

Inotuzumab ozogamicin studies

Conclusions

AML and NHL are generally effectively treated with cytotoxic agents in the first-line setting. Despite the chemosensitivity of these diseases and advances in treatment, the curability rates remain low. Although it has been shown that a higher dose of daunorubicin can have a beneficial effect on AML, recent studies have suggested a plateau in the dose-response relationship of conventional cytotoxics, likely due to a higher incidence of toxic effects (58–61). Efficient drug delivery to malignant cells through ADCs minimizes drug exposure in normal tissues, increasing the therapeutic index of the attached cytotoxic drug. GO was the first drug to prove the ADC concept in the clinic, specifically in phase II studies that included substantial proportions of older patients with relapsed AML. In contrast, it has thus far failed to show clinical benefit in first-line treatment in combination with standard chemotherapy. ADCs may have a narrow therapeutic window when combined with a highly toxic, multiagent induction regimen in an unselected population. Inotuzumab ozogamicin has shown remarkable clinical activity in relapsed/refractory B-cell NHL, and phase III evaluation has begun. Two important questions remain unanswered: Are there better ways to dose these drugs, which are subjected to target-mediated disposition, and how should they be integrated with conventional chemotherapy to provide the most effective and best-tolerated treatment options? GO and inotuzumab ozogamicin are molecularly targeted agents that clearly suggest a new paradigm. As we steadily move toward the goal of personalized medicine, these kinds of agents will show a benefit in selected subpopulations based on the expression of specific targets (42).

Disclosure of Potential Conflicts of Interest

Alejandro D. Ricart is employed by and has an ownership interest in Pfizer Inc.

Acknowledgments

The author thanks Mark Shapiro (global medical affairs lead for hematology programs at Pfizer) and Erik Vandendries (clinical lead for inotuzumab ozogamicin at Pfizer) for their critical reading of the article and helpful suggestions. The author thanks Leonard A. Mattano for editorial suggestions.

  • Received April 28, 2011.
  • Revision received July 7, 2011.
  • Accepted August 1, 2011.

References

  1. 1.↵
    1. Keizer RJ,
    2. Huitema AD,
    3. Schellens JH,
    4. Beijnen JH
    . Clinical pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet 2010;49:493–507.
    OpenUrlCrossRefPubMed
  2. 2.↵
    1. LoRusso PM,
    2. Weiss D,
    3. Guardino E,
    4. Girish S,
    5. Sliwkowski MX
    . Trastuzumab emtansine: a unique antibody-drug conjugate in development for human epidermal growth factor receptor 2–positive cancer. Clin Cancer Res 2011;17:6437–47.
    OpenUrlAbstract/FREE Full Text
  3. 3.↵
    1. Katz J,
    2. Janik JE,
    3. Younes A
    . Brentuximab vedotin (SGN-35). Clin Cancer Res 2011;17:6428–36.
    OpenUrlAbstract/FREE Full Text
  4. 4.↵
    1. Blanc V,
    2. Bousseau A,
    3. Caron A,
    4. Carrez C,
    5. Lutz RJ,
    6. Lambert JM
    . SAR3419: an anti-CD19-maytansinoid immunoconjugate for the treatment of B-cell malignancies. Clin Cancer Res 2011;17:6448–58.
    OpenUrlAbstract/FREE Full Text
  5. 5.↵
    1. Kreitman RJ,
    2. Pastan I
    . Antibody fusion proteins: anti-CD22 recombinant immunotoxin moxetumomab pasudotox. Clin Cancer Res 2011;17:6398–405.
    OpenUrlAbstract/FREE Full Text
  6. 6.↵
    1. Steiner M,
    2. Neri D
    . Antibody-radionuclide conjugates for cancer therapy: historical considerations and new trends. Clin Cancer Res 2011;17:6406–16.
    OpenUrlAbstract/FREE Full Text
  7. 7.↵
    1. Teicher BA,
    2. Chari RVJ
    . Antibody conjugate therapeutics: challenges and potential. Clin Cancer Res 2011;17:6389–97.
    OpenUrlAbstract/FREE Full Text
  8. 8.↵
    1. O';Reilly MK,
    2. Paulson JC
    . Siglecs as targets for therapy in immune-cell-mediated disease. Trends Pharmacol Sci 2009;30:240–8.
    OpenUrlCrossRefPubMed
  9. 9.↵
    1. Crocker PR,
    2. Paulson JC,
    3. Varki A
    . Siglecs and their roles in the immune system. Nat Rev Immunol 2007;7:255–66.
    OpenUrlCrossRefPubMed
  10. 10.↵
    1. Beers SA,
    2. Chan CH,
    3. French RR,
    4. Cragg MS,
    5. Glennie MJ
    . CD20 as a target for therapeutic type I and II monoclonal antibodies. Semin Hematol 2010;47:107–14.
    OpenUrlCrossRefPubMed
  11. 11.↵
    1. Hamann PR,
    2. Hinman LM,
    3. Hollander I,
    4. Beyer CF,
    5. Lindh D,
    6. Holcomb R,
    7. et al.
    Gemtuzumab ozogamicin, a potent and selective anti-CD33 antibody-calicheamicin conjugate for treatment of acute myeloid leukemia. Bioconjug Chem 2002;13:47–58.
    OpenUrlCrossRefPubMed
  12. 12.↵
    1. Zein N,
    2. Sinha AM,
    3. McGahren WJ,
    4. Ellestad GA
    . Calicheamicin gamma 1I: an antitumor antibiotic that cleaves double-stranded DNA site specifically. Science 1988;240:1198–201.
    OpenUrlAbstract/FREE Full Text
  13. 13.↵
    1. van Der Velden VH,
    2. te Marvelde JG,
    3. Hoogeveen PG,
    4. Bernstein ID,
    5. Houtsmuller AB,
    6. Berger MS,
    7. et al.
    Targeting of the CD33-calicheamicin immunoconjugate Mylotarg (CMA-676) in acute myeloid leukemia: in vivo and in vitro saturation and internalization by leukemic and normal myeloid cells. Blood 2001;97:3197–204.
    OpenUrlAbstract/FREE Full Text
  14. 14.↵
    1. Linenberger ML
    . CD33-directed therapy with gemtuzumab ozogamicin in acute myeloid leukemia: progress in understanding cytotoxicity and potential mechanisms of drug resistance. Leukemia 2005;19:176–82.
    OpenUrlCrossRefPubMed
  15. 15.↵
    1. Walter RB,
    2. Raden BW,
    3. Kamikura DM,
    4. Cooper JA,
    5. Bernstein ID
    . Influence of CD33 expression levels and ITIM-dependent internalization on gemtuzumab ozogamicin-induced cytotoxicity. Blood 2005;105:1295–302.
    OpenUrlAbstract/FREE Full Text
  16. 16.↵
    1. Sievers EL,
    2. Larson RA,
    3. Stadtmauer EA,
    4. Estey E,
    5. Löwenberg B,
    6. Dombret H,
    7. et al.
    Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukemia in first relapse. J Clin Oncol 2001;19:3244–54.
    OpenUrlAbstract/FREE Full Text
  17. 17.↵
    1. Burnett AK,
    2. Hills RK,
    3. Milligan D,
    4. Kjeldsen L,
    5. Kell J,
    6. Russell NH,
    7. et al.
    Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. J Clin Oncol 2011;29:369–77.
    OpenUrlAbstract/FREE Full Text
  18. 18.↵
    1. Jedema I,
    2. Barge RM,
    3. van der Velden VH,
    4. Nijmeijer BA,
    5. van Dongen JJ,
    6. Willemze R,
    7. et al.
    Internalization and cell cycle-dependent killing of leukemic cells by gemtuzumab ozogamicin: rationale for efficacy in CD33-negative malignancies with endocytic capacity. Leukemia 2004;18:316–25.
    OpenUrlCrossRefPubMed
  19. 19.↵
    1. Walter RB,
    2. Gooley TA,
    3. van der Velden VH,
    4. Loken MR,
    5. van Dongen JJ,
    6. Flowers DA,
    7. et al.
    CD33 expression and P-glycoprotein-mediated drug efflux inversely correlate and predict clinical outcome in patients with acute myeloid leukemia treated with gemtuzumab ozogamicin monotherapy. Blood 2007;109:4168–70.
    OpenUrlAbstract/FREE Full Text
  20. 20.↵
    1. Linenberger ML,
    2. Hong T,
    3. Flowers D,
    4. Sievers EL,
    5. Gooley TA,
    6. Bennett JM,
    7. et al.
    Multidrug-resistance phenotype and clinical responses to gemtuzumab ozogamicin. Blood 2001;98:988–94.
    OpenUrlAbstract/FREE Full Text
  21. 21.↵
    1. Dowell JA,
    2. Korth-Bradley J,
    3. Liu H,
    4. King SP,
    5. Berger MS
    . Pharmacokinetics of gemtuzumab ozogamicin, an antibody-targeted chemotherapy agent for the treatment of patients with acute myeloid leukemia in first relapse. J Clin Pharmacol 2001;41:1206–14.
    OpenUrlCrossRefPubMed
  22. 22.↵
    1. Buckwalter M,
    2. Dowell JA,
    3. Korth-Bradley J,
    4. Gorovits B,
    5. Mayer PR
    . Pharmacokinetics of gemtuzumab ozogamicin as a single-agent treatment of pediatric patients with refractory or relapsed acute myeloid leukemia. J Clin Pharmacol 2004;44:873–80.
    OpenUrlCrossRefPubMed
  23. 23.↵
    1. Korth-Bradley JM,
    2. Dowell JA,
    3. King SP,
    4. Liu H,
    5. Berger MS
    Mylotarg Study Group. Impact of age and gender on the pharmacokinetics of gemtuzumab ozogamicin. Pharmacotherapy 2001;21:1175–80.
    OpenUrlCrossRefPubMed
  24. 24.↵
    1. Sievers EL,
    2. Appelbaum FR,
    3. Spielberger RT,
    4. Forman SJ,
    5. Flowers D,
    6. Smith FO,
    7. et al.
    Selective ablation of acute myeloid leukemia using antibody-targeted chemotherapy: a phase I study of an anti-CD33 calicheamicin immunoconjugate. Blood 1999;93:3678–84.
    OpenUrlAbstract/FREE Full Text
  25. 25.↵
    1. Bross PF,
    2. Beitz J,
    3. Chen G,
    4. Chen XH,
    5. Duffy E,
    6. Kieffer L,
    7. et al.
    Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia. Clin Cancer Res 2001;7:1490–6.
    OpenUrlAbstract/FREE Full Text
  26. 26.↵
    1. McDonald GB
    . Management of hepatic sinusoidal obstruction syndrome following treatment with gemtuzumab ozogamicin (Mylotarg). Clin Lymphoma 2002;2[Suppl 1]:S35–9.
    OpenUrlCrossRefPubMed
  27. 27.↵
    1. Rajvanshi P,
    2. Shulman HM,
    3. Sievers EL,
    4. McDonald GB
    . Hepatic sinusoidal obstruction after gemtuzumab ozogamicin (Mylotarg) therapy. Blood 2002;99:2310–4.
    OpenUrlAbstract/FREE Full Text
  28. 28.↵
    1. Nabhan C,
    2. Rundhaugen L,
    3. Jatoi M,
    4. Riley MB,
    5. Boehlke L,
    6. Peterson LC,
    7. et al.
    Gemtuzumab ozogamicin (MylotargTM) is infrequently associated with sinusoidal obstructive syndrome/veno-occlusive disease. Ann Oncol 2004;15:1231–6.
    OpenUrlAbstract/FREE Full Text
  29. 29.↵
    1. Larson RA,
    2. Sievers EL,
    3. Stadtmauer EA,
    4. Löwenberg B,
    5. Estey EH,
    6. Dombret H,
    7. et al.
    Final report of the efficacy and safety of gemtuzumab ozogamicin (Mylotarg) in patients with CD33-positive acute myeloid leukemia in first recurrence. Cancer 2005;104:1442–52.
    OpenUrlCrossRefPubMed
  30. 30.↵
    1. Wadleigh M,
    2. Richardson PG,
    3. Zahrieh D,
    4. Lee SJ,
    5. Cutler C,
    6. Ho V,
    7. et al.
    Prior gemtuzumab ozogamicin exposure significantly increases the risk of veno-occlusive disease in patients who undergo myeloablative allogeneic stem cell transplantation. Blood 2003;102:1578–82.
    OpenUrlAbstract/FREE Full Text
  31. 31.↵
    1. van der Velden VH,
    2. Boeckx N,
    3. Jedema I,
    4. te Marvelde JG,
    5. Hoogeveen PG,
    6. Boogaerts M,
    7. et al.
    High CD33-antigen loads in peripheral blood limit the efficacy of gemtuzumab ozogamicin (Mylotarg) treatment in acute myeloid leukemia patients. Leukemia 2004;18:983–8.
    OpenUrlCrossRefPubMed
  32. 32.↵
    1. Lo Coco F,
    2. Ammatuna E,
    3. Noguera N
    . Treatment of acute promyelocytic leukemia with gemtuzumab ozogamicin. Clin Adv Hematol Oncol 2006;4:57–62, 76–7.
    OpenUrlPubMed
  33. 33.↵
    1. Takeshita A,
    2. Shinjo K,
    3. Naito K,
    4. Matsui H,
    5. Sahara N,
    6. Shigeno K,
    7. et al.
    Efficacy of gemtuzumab ozogamicin on ATRA- and arsenic-resistant acute promyelocytic leukemia (APL) cells. Leukemia 2005;19:1306–11.
    OpenUrlCrossRefPubMed
  34. 34.↵
    1. Candoni A,
    2. Damiani D,
    3. Michelutti A,
    4. Masolini P,
    5. Michieli M,
    6. Michelutti T,
    7. et al.
    Clinical characteristics, prognostic factors and multidrug-resistance related protein expression in 36 adult patients with acute promyelocytic leukemia. Eur J Haematol 2003;71:1–8.
    OpenUrlCrossRefPubMed
  35. 35.↵
    1. Ravandi F,
    2. Estey E,
    3. Jones D,
    4. Faderl S,
    5. O';Brien S,
    6. Fiorentino J,
    7. et al.
    Effective treatment of acute promyelocytic leukemia with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab ozogamicin. J Clin Oncol 2009;27:504–10.
    OpenUrlAbstract/FREE Full Text
  36. 36.↵
    1. Aribi A,
    2. Kantarjian HM,
    3. Estey EH,
    4. Koller CA,
    5. Thomas DA,
    6. Kornblau SM,
    7. et al.
    Combination therapy with arsenic trioxide, all-trans retinoic acid, and gemtuzumab ozogamicin in recurrent acute promyelocytic leukemia. Cancer 2007;109:1355–9.
    OpenUrlCrossRefPubMed
  37. 37.↵
    1. Estey E,
    2. Garcia-Manero G,
    3. Ferrajoli A,
    4. Faderl S,
    5. Verstovsek S,
    6. Jones D,
    7. et al.
    Use of all-trans retinoic acid plus arsenic trioxide as an alternative to chemotherapy in untreated acute promyelocytic leukemia. Blood 2006;107:3469–73.
    OpenUrlAbstract/FREE Full Text
  38. 38.↵
    1. Lo-Coco F,
    2. Cimino G,
    3. Breccia M,
    4. Noguera NI,
    5. Diverio D,
    6. Finolezzi E,
    7. et al.
    Gemtuzumab ozogamicin (Mylotarg) as a single agent for molecularly relapsed acute promyelocytic leukemia. Blood 2004;104:1995–9.
    OpenUrlAbstract/FREE Full Text
  39. 39.↵
    1. Estey EH,
    2. Giles FJ,
    3. Beran M,
    4. O';Brien S,
    5. Pierce SA,
    6. Faderl SH,
    7. et al.
    Experience with gemtuzumab ozogamycin (“Mylotarg”) and all-trans retinoic acid in untreated acute promyelocytic leukemia. Blood 2002;99:4222–4.
    OpenUrlAbstract/FREE Full Text
  40. 40.↵
    1. Petti MC,
    2. Pinazzi MB,
    3. Diverio D,
    4. Romano A,
    5. Petrucci MT,
    6. De Santis S,
    7. et al.
    Prolonged molecular remission in advanced acute promyelocytic leukaemia after treatment with gemtuzumab ozogamicin (Mylotarg CMA-676). Br J Haematol 2001;115:63–5.
    OpenUrlCrossRefPubMed
  41. 41.
    1. Petersdorf S,
    2. Kopecky K,
    3. Stuart RK,
    4. Larson RA,
    5. Nevill TJ,
    6. Stenke L,
    7. et al.
    Preliminary results of Southwest Oncology Group Study S0106: an international intergroup phase 3 randomized trial comparing the addition of gemtuzumab ozogamicin to standard induction therapy versus standard induction therapy followed by a second randomization to post-consolidation gemtuzumab ozogamicin versus no additional therapy for previously untreated acute myeloid leukemia. Blood 2009;114:790.
    OpenUrl
  42. 42.↵
    1. Ravandi F
    . Gemtuzumab ozogamicin: one size does not fit all—the case for personalized therapy. J Clin Oncol 2011;29:349–51.
    OpenUrlFREE Full Text
  43. 43.↵
    1. Cesano A,
    2. Gayko U
    . CD22 as a target of passive immunotherapy. Semin Oncol 2003;30:253–7.
    OpenUrlCrossRefPubMed
  44. 44.↵
    1. Mason DY,
    2. Stein H,
    3. Gerdes J,
    4. Pulford KA,
    5. Ralfkiaer E,
    6. Falini B,
    7. et al.
    Value of monoclonal anti-CD22 (p135) antibodies for the detection of normal and neoplastic B lymphoid cells. Blood 1987;69:836–40.
    OpenUrlAbstract/FREE Full Text
  45. 45.↵
    1. Olejniczak SH,
    2. Stewart CC,
    3. Donohue K,
    4. Czuczman MS
    . A quantitative exploration of surface antigen expression in common B-cell malignancies using flow cytometry. Immunol Invest 2006;35:93–114.
    OpenUrlCrossRefPubMed
  46. 46.↵
    1. DiJoseph JF,
    2. Armellino DC,
    3. Boghaert ER,
    4. Khandke K,
    5. Dougher MM,
    6. Sridharan L,
    7. et al.
    Antibody-targeted chemotherapy with CMC-544: a CD22-targeted immunoconjugate of calicheamicin for the treatment of B-lymphoid malignancies. Blood 2004;103:1807–14.
    OpenUrlAbstract/FREE Full Text
  47. 47.↵
    1. DiJoseph JF,
    2. Goad ME,
    3. Dougher MM,
    4. Boghaert ER,
    5. Kunz A,
    6. Hamann PR,
    7. et al.
    Potent and specific antitumor efficacy of CMC-544, a CD22-targeted immunoconjugate of calicheamicin, against systemically disseminated B-cell lymphoma. Clin Cancer Res 2004;10:8620–9.
    OpenUrlAbstract/FREE Full Text
  48. 48.↵
    1. Takeshita A,
    2. Shinjo K,
    3. Yamakage N,
    4. Ono T,
    5. Hirano I,
    6. Matsui H,
    7. et al.
    CMC-544 (inotuzumab ozogamicin) shows less effect on multidrug resistant cells: analyses in cell lines and cells from patients with B-cell chronic lymphocytic leukaemia and lymphoma. Br J Haematol 2009;146:34–43.
    OpenUrlCrossRefPubMed
  49. 49.↵
    1. DiJoseph JF,
    2. Dougher MM,
    3. Evans DY,
    4. Zhou BB,
    5. Damle NK
    . Preclinical anti-tumor activity of antibody-targeted chemotherapy with CMC-544 (inotuzumab ozogamicin), a CD22-specific immunoconjugate of calicheamicin, compared with non-targeted combination chemotherapy with CVP or CHOP. Cancer Chemother Pharmacol 2011;67:741–9.
    OpenUrlCrossRefPubMed
  50. 50.↵
    1. DiJoseph JF,
    2. Dougher MM,
    3. Kalyandrug LB,
    4. Armellino DC,
    5. Boghaert ER,
    6. Hamann PR,
    7. et al.
    Antitumor efficacy of a combination of CMC-544 (inotuzumab ozogamicin), a CD22-targeted cytotoxic immunoconjugate of calicheamicin, and rituximab against non-Hodgkin's B-cell lymphoma. Clin Cancer Res 2006;12:242–9.
    OpenUrlAbstract/FREE Full Text
  51. 51.↵
    1. Takeshita A,
    2. Yamakage N,
    3. Shinjo K,
    4. Ono T,
    5. Hirano I,
    6. Nakamura S,
    7. et al.
    CMC-544 (inotuzumab ozogamicin), an anti-CD22 immuno-conjugate of calicheamicin, alters the levels of target molecules of malignant B-cells. Leukemia 2009;23:1329–36.
    OpenUrlCrossRefPubMed
  52. 52.↵
    1. Advani A,
    2. Coiffier B,
    3. Czuczman MS,
    4. Dreyling M,
    5. Foran J,
    6. Gine E,
    7. et al.
    Safety, pharmacokinetics, and preliminary clinical activity of inotuzumab ozogamicin, a novel immunoconjugate for the treatment of B-cell non-Hodgkin's lymphoma: results of a phase I study. J Clin Oncol 2010;28:2085–93.
    OpenUrlAbstract/FREE Full Text
  53. 53.↵
    1. Dijoseph JF,
    2. Dougher MM,
    3. Armellino DC,
    4. Evans DY,
    5. Damle NK
    . Therapeutic potential of CD22-specific antibody-targeted chemotherapy using inotuzumab ozogamicin (CMC-544) for the treatment of acute lymphoblastic leukemia. Leukemia 2007;21:2240–5.
    OpenUrlCrossRefPubMed
  54. 54.↵
    1. Ogura M,
    2. Tobinai K,
    3. Hatake K,
    4. Uchida T,
    5. Kasai M,
    6. Oyama T,
    7. et al.
    Phase I study of inotuzumab ozogamicin (CMC-544) in Japanese patients with follicular lymphoma pretreated with rituximab-based therapy. Cancer Sci 2010;101:1840–5.
    OpenUrlCrossRefPubMed
  55. 55.↵
    1. Verhoef G,
    2. Dang N,
    3. Smith M,
    4. Offner F,
    5. Johnson P,
    6. Rohatiner A,
    7. et al.
    Anti-CD22 immunoconjugate inotuzumab ozogamicin (CMC-544) + rituximab: clinical activity in patients with relapsed/refractory follicular or aggressive lymphomas. Haematologica 2010;95(suppl 2):238 [abstr 0573].
    OpenUrl
  56. 56.↵
    1. Goy A,
    2. Leach J,
    3. Ehmann WC,
    4. Ando K,
    5. Hatake K,
    6. Tobinai K,
    7. et al.
    Inotuzumab ozogamicin (CMC-544) in patients with indolent B-Cell NHL that is refractory to rituximab alone, rituximab and chemotherapy, or radioimmunotherapy: preliminary safety and efficacy from a phase 2 trial. Blood 2010;116:430.
    OpenUrl
  57. 57.↵
    1. Fayad L,
    2. Patel H,
    3. Verhoef G,
    4. Smith MR,
    5. Johnson PWM,
    6. Czuczman MS,
    7. et al.
    Safety and clinical activity of the anti-CD22 immunoconjugate inotuzumab ozogamicin (CMC-544) in combination with rituximab in follicular lymphoma or diffuse large B-cell lymphoma: preliminary report of a phase 1/2 study. Blood 2008;112:266.
    OpenUrl
  58. 58.↵
    1. Löwenberg B,
    2. Ossenkoppele GJ,
    3. van Putten W,
    4. Schouten HC,
    5. Graux C,
    6. Ferrant A,
    7. et al.
    High-dose daunorubicin in older patients with acute myeloid leukemia. N Engl J Med 2009;361:1235–48. Erratum in: N Engl J Med 2010;362:1155.
    OpenUrlCrossRefPubMed
  59. 59.↵
    1. Fernandez HF,
    2. Sun Z,
    3. Yao X,
    4. Litzow MR,
    5. Luger SM,
    6. Paietta EM,
    7. et al.
    Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med 2009;361:1249–59.
    OpenUrlCrossRefPubMed
  60. 60.↵
    1. Verdonck LF,
    2. Notenboom A,
    3. de Jong DD,
    4. MacKenzie MA,
    5. Verhoef GE,
    6. Kramer MH,
    7. et al.
    Intensified 12-week CHOP (I-CHOP) plus G-CSF compared with standard 24-week CHOP (CHOP-21) for patients with intermediate-risk aggressive non-Hodgkin lymphoma: a phase 3 trial of the Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON). Blood 2007;109:2759–66.
    OpenUrlAbstract/FREE Full Text
  61. 61.↵
    1. Löwenberg B,
    2. Pabst T,
    3. Vellenga E,
    4. van Putten W,
    5. Schouten HC,
    6. Graux C,
    7. et al.
    Cytarabine dose for acute myeloid leukemia. N Engl J Med 2011;364:1027–36.
    OpenUrlCrossRefPubMed
  62. 62.
    1. Taksin AL,
    2. Legrand O,
    3. Raffoux E,
    4. de Revel T,
    5. Thomas X,
    6. Contentin N,
    7. et al.
    High efficacy and safety profile of fractionated doses of Mylotarg as induction therapy in patients with relapsed acute myeloblastic leukemia: a prospective study of the alfa group. Leukemia 2007;21:66–71.
    OpenUrlCrossRefPubMed
  63. 63.
    1. Piccaluga PP,
    2. Martinelli G,
    3. Rondoni M,
    4. Malagola M,
    5. Gaitani S,
    6. Isidori A,
    7. et al.
    Gemtuzumab ozogamicin for relapsed and refractory acute myeloid leukemia and myeloid sarcomas. Leuk Lymphoma 2004;45:1791–5.
    OpenUrlCrossRefPubMed
  64. 64.
    1. Amadori S,
    2. Suciu S,
    3. Selleslag D,
    4. Stasi R,
    5. Alimena G,
    6. Baila L,
    7. et al.
    Randomized trial of two schedules of low-dose gemtuzumab ozogamicin as induction monotherapy for newly diagnosed acute myeloid leukaemia in older patients not considered candidates for intensive chemotherapy. A phase II study of the EORTC and GIMEMA leukaemia groups (AML-19). Br J Haematol 2010;149:376–82.
    OpenUrlCrossRefPubMed
  65. 65.
    1. Amadori S,
    2. Suciu S,
    3. Stasi R,
    4. Willemze R,
    5. Mandelli F,
    6. Selleslag D,
    7. et al.
    Gemtuzumab ozogamicin (Mylotarg) as single-agent treatment for frail patients 61 years of age and older with acute myeloid leukemia: final results of AML-15B, a phase 2 study of the European Organisation for Research and Treatment of Cancer and Gruppo Italiano Malattie Ematologiche dell';Adulto Leukemia Groups. Leukemia 2005;19:1768–73.
    OpenUrlCrossRefPubMed
  66. 66.
    1. Nabhan C,
    2. Rundhaugen LM,
    3. Riley MB,
    4. Rademaker A,
    5. Boehlke L,
    6. Jatoi M,
    7. et al.
    Phase II pilot trial of gemtuzumab ozogamicin (GO) as first line therapy in acute myeloid leukemia patients age 65 or older. Leuk Res 2005;29:53–7.
    OpenUrlCrossRefPubMed
  67. 67.
    1. Stone RM,
    2. Moser B,
    3. Sanford B,
    4. Schulman P,
    5. Kolitz JE,
    6. Allen S,
    7. et al.
    High dose cytarabine plus gemtuzumab ozogamicin for patients with relapsed or refractory acute myeloid leukemia: Cancer and Leukemia Group B study 19902. Leuk Res 2011;35:329–33.
    OpenUrlCrossRefPubMed
  68. 68.
    1. Chevallier P,
    2. Delaunay J,
    3. Turlure P,
    4. Pigneux A,
    5. Hunault M,
    6. Garand R,
    7. et al.
    Long-term disease-free survival after gemtuzumab, intermediate-dose cytarabine, and mitoxantrone in patients with CD33(+) primary resistant or relapsed acute myeloid leukemia. J Clin Oncol 2008;26:5192–7.
    OpenUrlAbstract/FREE Full Text
  69. 69.
    1. Tsimberidou A,
    2. Cortes J,
    3. Thomas D,
    4. Garcia-Manero G,
    5. Verstovsek S,
    6. Faderl S,
    7. et al.
    Gemtuzumab ozogamicin, fludarabine, cytarabine and cyclosporine combination regimen in patients with CD33+ primary resistant or relapsed acute myeloid leukemia. Leuk Res 2003;27:893–7.
    OpenUrlCrossRefPubMed
  70. 70.
    1. Candoni A,
    2. Martinelli G,
    3. Toffoletti E,
    4. Chiarvesio A,
    5. Tiribelli M,
    6. Malagola M,
    7. et al.
    Gemtuzumab-ozogamicin in combination with fludarabine, cytarabine, idarubicin (FLAI-GO) as induction therapy in CD33-positive AML patients younger than 65 years. Leuk Res 2008;32:1800–8.
    OpenUrlCrossRefPubMed
  71. 71.
    1. Eom KS,
    2. Kim HJ,
    3. Min WS,
    4. Lee S,
    5. Min CK,
    6. Cho BS,
    7. et al.
    Gemtuzumab ozogamicin in combination with attenuated doses of standard induction chemotherapy can successfully induce complete remission without increasing toxicity in patients with acute myeloid leukemia aged 55 or older. Eur J Haematol 2007;79:398–404.
    OpenUrlCrossRefPubMed
  72. 72.
    1. Tsimberidou A,
    2. Estey E,
    3. Cortes J,
    4. Thomas D,
    5. Faderl S,
    6. Verstovsek S,
    7. et al.
    Gemtuzumab, fludarabine, cytarabine, and cyclosporine in patients with newly diagnosed acute myelogenous leukemia or high-risk myelodysplastic syndromes. Cancer 2003;97:1481–7.
    OpenUrlCrossRefPubMed
  73. 73.
    1. Kell WJ,
    2. Burnett AK,
    3. Chopra R,
    4. Yin JA,
    5. Clark RE,
    6. Rohatiner A,
    7. et al.
    A feasibility study of simultaneous administration of gemtuzumab ozogamicin with intensive chemotherapy in induction and consolidation in younger patients with acute myeloid leukemia. Blood 2003;102:4277–83.
    OpenUrlAbstract/FREE Full Text
  74. 74.
    1. Amadori S,
    2. Suciu S,
    3. Willemze R,
    4. Mandelli F,
    5. Selleslag D,
    6. Stauder R,
    7. et al.
    Sequential administration of gemtuzumab ozogamicin and conventional chemotherapy as first line therapy in elderly patients with acute myeloid leukemia: a phase II study (AML-15) of the EORTC and GIMEMA leukemia groups. Haematologica 2004;89:950–6.
    OpenUrlAbstract/FREE Full Text
  75. 75.
    1. Clavio M,
    2. Vignolo L,
    3. Albarello A,
    4. Varaldo R,
    5. Pierri I,
    6. Catania G,
    7. et al.
    Adding low-dose gemtuzumab ozogamicin to fludarabine, Ara-C and idarubicin (MY-FLAI) may improve disease-free and overall survival in elderly patients with non-M3 acute myeloid leukaemia: results of a prospective, pilot, multi-centre trial and comparison with a historical cohort of patients. Br J Haematol 2007;138:186–95.
    OpenUrlCrossRefPubMed
  76. 76.
    1. Litzow MR,
    2. Othus M,
    3. Cripe LD,
    4. Gore SD,
    5. Lazarus HM,
    6. Lee SJ,
    7. et al.
    Failure of three novel regimens to improve outcome for patients with relapsed or refractory acute myeloid leukaemia: a report from the Eastern Cooperative Oncology Group. Br J Haematol 2010;148:217–25.
    OpenUrlCrossRefPubMed
  77. 77.
    1. Löwenberg B,
    2. Beck J,
    3. Graux C,
    4. van Putten W,
    5. Schouten HC,
    6. Verdonck LF,
    7. et al.
    Gemtuzumab ozogamicin as postremission treatment in AML at 60 years of age or more: results of a multicenter phase 3 study. Blood 2010;115:2586–91.
    OpenUrlAbstract/FREE Full Text
  78. 78.
    1. Wagner-Johnston N,
    2. Goy A,
    3. Feldman T,
    4. Goh YT,
    5. Suh C,
    6. Sweetenham JW,
    7. et al.
    Anti-CD22 immunoconjugate inotuzumab ozogamicin (CMC-544) + rituximab in relapsed DLBCL patients followed by stem cell transplantation: preliminary safety and efficacy. Blood 2010;116:2883.
    OpenUrl
  79. 79.
    1. Hatake K,
    2. Ogura M,
    3. Ando K,
    4. Tokushige K,
    5. Ono C,
    6. Vandendries ER,
    7. et al.
    Phase 1 study of anti-CD22 immunoconjugate inotuzumab ozogamicin (CMC-544) plus rituximab in Japanese patients with relapsed/refractory B-cell non-Hodgkin lymphoma. Blood 2010;116:2872.
    OpenUrl
View Abstract
Back to top
Clinical Cancer Research: 17 (20)
October 2011
Volume 17, Issue 20

Sign up for alerts

View this article with LENS

Open full page PDF
Article Alerts
Email Article
Citation Tools
Antibody-Drug Conjugates of Calicheamicin Derivative: Gemtuzumab Ozogamicin and Inotuzumab Ozogamicin
Alejandro D. Ricart
Clin Cancer Res October 15 2011 (17) (20) 6417-6427; DOI: 10.1158/1078-0432.CCR-11-0486
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo

Jump to section

Advertisement