Gemtuzumab ozogamicin: is there room for salvage?

Abstract

over days 2-3), and intrathecal methotrexate (15 mg/day on day 1). Although initially successful, the patient later relapsed with an increase in the size and number of the cerebral lesions. Oral dasatinib (70 mg twice per day) was started and led to a complete regression of lesions visible on MRI and neurologic disease. The patient is currently in remission (Ͼ 12 months) with no measurable monoclonal lymphocyte population in blood and bone marrow on continuous therapy.Pitini et al 2 and others 3 initially reported responses to dasatinib in patients with CLL, although subsequent phase 2 clinical trials in relapsed CLL demonstrated only moderate activity. 5 This is the first report of dasatinib treatment in central nervous system B-CLL and might serve as a proof of concept for future cases. In vitro data suggest that del(17p) mutated CLL and those with unmutated immunoglobulin heavy chains (IgVHs) might be especially sensitive to dasatinib. 2,5,6 Unfortunately, IgVH mutational analysis was not initially performed. Dasatinib CSF concentration is reported to reach only 5% to 28% of plasma concentrations in humans. 4 Still, the effect in this case was clinically meaningful and lasting. Further clinical investigation of dasatinib treatment in B-CLL with CNS involvement is warranted. Georg Russwurm To the editor:Gemtuzumab ozogamicin: is there room for salvage?On May 17, 2000, gemtuzumab ozogamicin received marketing approval from the US Food and Drug Administration (FDA) under accelerated approval regulations for the treatment of patients with CD33-positive acute myeloid leukemia (AML) in first relapse who are 60 years of age or older and who are not considered candidates for cytotoxic chemotherapy. 1 The data supporting this application included 3 open-label studies that enrolled 157 patients at least 60 years of age in whom an overall response rate of 24% (12% CR ϩ 12% CRp) was observed. On June 21, 2010, the FDA and Pfizer announced that this drug would be voluntarily withdrawn from the market due to failure of 2 confirmatory clinical trials to demonstrate clinical benefit. Of note, the confirmatory trials examined gemtuzumab as an addition to standard induction chemotherapy in newly diagnosed patients up to 70 years of age, rather than in a relapsed or refractory older population. To those familiar with other attempts at improving outcomes in patients with newly diagnosed AML and with the hepatic toxicity of the approved dosing regimen of gemtuzumab, the failure of gemtuzumab to provide survival benefit when combined with anthracycline and cytarabine was not surprising. [2][3][4] It is, therefore, appropriate for the drug to be withdrawn from the market at this time given the accelerated regulatory pathway agreed upon previously. However, questions remain. Is there a role for this agent in a certain population of patients? Is there a safer method for administering the drug?Data from uncontrolled studies clearly indicate that the drug has single-agent activity in the setting of relapsed or refractory AML in a...

A Unique Human Immunoglobulin Heavy Chain Variable Domain-Only CD33 CAR for the Treatment of Acute Myeloid Leukemia

“…Chemotherapy regimens are only partially effective, and often require bone marrow transplant and multiple rounds of consolidation therapy. Moreover, many patients are refractory to this course of treatment, and the overall 5-year survival remains below 30% for all patients, and below 5% for older patients, ( 36 ) among the lowest current survival percentages of all hematologic malignancies (SEER statistics, seer.cancer.gov). The advent of targeted immunotherapy, as represented by experimental CAR-T approaches and the approval of anti-CD33 antibody-drug conjugates, brings new hope to improve on these response rates.…”

“…Experimental treatments targeting CD33 antigen, including anti CD33 antibodies, CD33-CD3 bispecific T cell engagers (BiTEs) and chimeric antigen receptors are often hampered by severe toxicity and low efficacy ( 11 – 13 , 36 , 39 ). Gemtuzumab Ozogamycin (GO), was recently reintroduced to clinical practice with modified treatment regimens, in order to improve over previous experience with this agent, which showed high toxicity and failed to prove clinical benefit, leading to the withdrawal of GO from the market in year 2010 ( 39 ).…”

A Unique Human Immunoglobulin Heavy Chain Variable Domain-Only CD33 CAR for the Treatment of Acute Myeloid Leukemia

“…Chemotherapy regimens are only partially effective, and often require bone marrow transplant and multiple rounds of consolidation therapy. Moreover, many patients are refractory to this course of treatment, and the overall 5-year survival remains below 30% for all patients, and below 5% for older patients, ( 36 ) among the lowest current survival percentages of all hematologic malignancies (SEER statistics, seer.cancer.gov). The advent of targeted immunotherapy, as represented by experimental CAR-T approaches and the approval of anti-CD33 antibody-drug conjugates, brings new hope to improve on these response rates.…”

“…Experimental treatments targeting CD33 antigen, including anti CD33 antibodies, CD33-CD3 bispecific T cell engagers (BiTEs) and chimeric antigen receptors are often hampered by severe toxicity and low efficacy ( 11 – 13 , 36 , 39 ). Gemtuzumab Ozogamycin (GO), was recently reintroduced to clinical practice with modified treatment regimens, in order to improve over previous experience with this agent, which showed high toxicity and failed to prove clinical benefit, leading to the withdrawal of GO from the market in year 2010 ( 39 ).…”

Induction ofDNAstrand breaks is critical to predict the cytotoxicity of gemtuzumab ozogamicin against leukemic cells

“…For the advancement of cancer treatment, individualized chemotherapy is necessary, based on the understanding of the cellular biology of each patient's cancer cells at the molecular level. Clinical studies suggest that GO should be used in individualized regimens for specific AML subsets and not for all patients . Sensitivity tests measuring GO‐induced DNA strand breaks may predict GO's clinical efficacy prior to treatment.…”

A new Leukemia Prognostic Scoring System for refractory/relapsed adult acute myelogeneous leukaemia patients: a GOELAMS study

“…This is of crucial importance as the US Food and Drug Administration has recently announced the withdrawal of the GO because of concerns about the product's safety and the clinical benefit to patients enrolled in trials. Although we are still convinced, with others, 15,16 that GO may have some interest in particular subgroups of AML patients, it seems that our new prognostic method for refractory/relapsed AML is broadly applicable to all intensive regimens, whether or not they contain GO.…”

A Unique Human Immunoglobulin Heavy Chain Variable Domain-Only CD33 CAR for the Treatment of Acute Myeloid Leukemia

“…Chemotherapy regimens are only partially effective, and often require bone marrow transplant and multiple rounds of consolidation therapy. Moreover, many patients are refractory to this course of treatment, and the overall 5-year survival remains below 30% for all patients, and below 5% for older patients, ( 36 ) among the lowest current survival percentages of all hematologic malignancies (SEER statistics, seer.cancer.gov). The advent of targeted immunotherapy, as represented by experimental CAR-T approaches and the approval of anti-CD33 antibody-drug conjugates, brings new hope to improve on these response rates.…”

“…Experimental treatments targeting CD33 antigen, including anti CD33 antibodies, CD33-CD3 bispecific T cell engagers (BiTEs) and chimeric antigen receptors are often hampered by severe toxicity and low efficacy ( 11 – 13 , 36 , 39 ). Gemtuzumab Ozogamycin (GO), was recently reintroduced to clinical practice with modified treatment regimens, in order to improve over previous experience with this agent, which showed high toxicity and failed to prove clinical benefit, leading to the withdrawal of GO from the market in year 2010 ( 39 ).…”

Induction ofDNAstrand breaks is critical to predict the cytotoxicity of gemtuzumab ozogamicin against leukemic cells

“…For the advancement of cancer treatment, individualized chemotherapy is necessary, based on the understanding of the cellular biology of each patient's cancer cells at the molecular level. Clinical studies suggest that GO should be used in individualized regimens for specific AML subsets and not for all patients . Sensitivity tests measuring GO‐induced DNA strand breaks may predict GO's clinical efficacy prior to treatment.…”

A new Leukemia Prognostic Scoring System for refractory/relapsed adult acute myelogeneous leukaemia patients: a GOELAMS study

“…This is of crucial importance as the US Food and Drug Administration has recently announced the withdrawal of the GO because of concerns about the product's safety and the clinical benefit to patients enrolled in trials. Although we are still convinced, with others, 15,16 that GO may have some interest in particular subgroups of AML patients, it seems that our new prognostic method for refractory/relapsed AML is broadly applicable to all intensive regimens, whether or not they contain GO.…”

A Unique Human Immunoglobulin Heavy Chain Variable Domain-Only CD33 CAR for the Treatment of Acute Myeloid Leukemia

“…Chemotherapy regimens are only partially effective, and often require bone marrow transplant and multiple rounds of consolidation therapy. Moreover, many patients are refractory to this course of treatment, and the overall 5-year survival remains below 30% for all patients, and below 5% for older patients, ( 36 ) among the lowest current survival percentages of all hematologic malignancies (SEER statistics, seer.cancer.gov). The advent of targeted immunotherapy, as represented by experimental CAR-T approaches and the approval of anti-CD33 antibody-drug conjugates, brings new hope to improve on these response rates.…”

“…Experimental treatments targeting CD33 antigen, including anti CD33 antibodies, CD33-CD3 bispecific T cell engagers (BiTEs) and chimeric antigen receptors are often hampered by severe toxicity and low efficacy ( 11 – 13 , 36 , 39 ). Gemtuzumab Ozogamycin (GO), was recently reintroduced to clinical practice with modified treatment regimens, in order to improve over previous experience with this agent, which showed high toxicity and failed to prove clinical benefit, leading to the withdrawal of GO from the market in year 2010 ( 39 ).…”

Induction ofDNAstrand breaks is critical to predict the cytotoxicity of gemtuzumab ozogamicin against leukemic cells

“…For the advancement of cancer treatment, individualized chemotherapy is necessary, based on the understanding of the cellular biology of each patient's cancer cells at the molecular level. Clinical studies suggest that GO should be used in individualized regimens for specific AML subsets and not for all patients . Sensitivity tests measuring GO‐induced DNA strand breaks may predict GO's clinical efficacy prior to treatment.…”

A new Leukemia Prognostic Scoring System for refractory/relapsed adult acute myelogeneous leukaemia patients: a GOELAMS study

“…This is of crucial importance as the US Food and Drug Administration has recently announced the withdrawal of the GO because of concerns about the product's safety and the clinical benefit to patients enrolled in trials. Although we are still convinced, with others, 15,16 that GO may have some interest in particular subgroups of AML patients, it seems that our new prognostic method for refractory/relapsed AML is broadly applicable to all intensive regimens, whether or not they contain GO.…”