Neoplasms

Blood and Lymph Conditions

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Rare Diseases

Leukemia

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Neoplasms by Histologic Type

Hematologic Diseases

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Acute Graft Versus Host Disease

Anti-Infective Agents

Antineoplastic Agents

All Drugs and Chemicals

Cytarabine

Idarubicin

Gemtuzumab

Antineoplastic Agents, Immunological

Immunotoxins

Immunoconjugates

Immunologic Factors

Cohort 1 version 1.0. GO: 6mg/m\^2 (maximum 10 mg), IV infusion, 2 hours, day 1. Idarubicin: 12 mg/m\^2, IV, 30 minutes, on days 2, 3, 4. Cytarabine: 100 mg/m\^2 IV days 1 to 7, to begin 4 hours after the administration of GO.

Cohort 1.0 version 2.0: GO: 3 mg/m\^2 (maximum 5 mg), IV infusion, 2 hours, day 1. Idarubicin: 12 mg/m\^2, IV, 30 minutes, on days 2, 3, 4. Cytarabine: 100 mg/m\^2 IV days 1 to 7, to begin 4 hours after the administration of GO.

Cohort 2: G-CSF: 150 mcg/m\^2, SC, days 0 to 7. GO: 3 mg/m\^2 (maximum 5 mg), IV infusion, 2 hours, day 1. Idarubicin: 12 mg/m\^2, IV, 30 minutes, on days 2, 3, 4. Cytarabine: 100 mg/m\^2 IV continuous infusion on days 1 to 7, to begin 4 hours later after the administration of GO.

Mylotarg

Jordi Sierra, MD

Acute myeloid leukemia (AML) is a neoplasm of immature hematopoietic cells (blasts) with altered ripening capacity. Due to excessive proliferation, the blasts displace normal hematopoietic cells and bone marrow failure appears. Leukemic cells also infiltrate extramedullary tissues.

Following the standard chemotherapy treatment, the CR rate achieved is around 65-75% for all patients and 15% lower when considering only patients over 65 years. Modifications to the standard regimen consist of replacing the DNR for a cytotoxic one, modifying the dose of ara-C or adding a third drug.

Gemtuzumab ozogamicin (Mylotarg ®) is an immunoconjugate between anti-CD33 antibody and a cytotoxic antitumor antibiotic, calicheamicin. Mylotarg ® antibody specifically binds to CD33, a sialic acid-dependent adhesion protein expressed in over 90% of LMA10. Mylotarg ® selectively transports the cytotoxic agent calicheamicin into leukemic cells and hematopoietic progenitors differentiated from the myelomonocytic line, while respecting the pluripotent hematopoietic stem cells. Calicheamicin is released only after the fixation of the antibody anti-CD33 and its internalization by the cell, after which binds to and damages the DNA.

Mylotarg ® is approved in the U.S. for the treatment of CD33 positive AML in first relapse, for patients older than 60 years non-candidates for other intensive treatment modalities.

Since the efficacy of Mylotarg ® is equivalent and its toxicity profile less than the conventional therapy, it is logical to conduct a phase II trial exploring the role of Mylotarg ® in the early stages of treatment of AML.

Previous experience with gemtuzumab ozogamicin in relapsed patients led to its use combined with induction chemotherapy. The aim was to improve the CR rate reached with the latter and reduce relapse after achieving greater leukemic cytoreduction.

Recent data from the HOVON group support that the administration of G-CSF before and during induction chemotherapy decreases the incidence of relapse in patients with AML, particularly those considered to have intermediate risk.

Everything mentioned above justifies to investigate the combination of GO combined with chemotherapy with IDR and ara-C in standard 3x7 scheme and analyze the effect of sensitization with G-CSF in patients with AML de novo. If the treatment proposed here is effective and presents an acceptable toxicity it should be investigated.

Prospective Study of Mylotarg and G-CSF in Acute Myeloid Leukemia Treatment

Treatment of de Novo Acute Myeloid Leukemia With the Combination of Idarubicin, Cytarabine, and Gemtuzumab Ozogamicin (Mylotarg ®), Associated or Not Priming With G-CSF. Prospective Study of Efficacy and Toxicity

Rate of patients that have obtained complete remission. Complete remission is defined as, bone marrow normocellular or slightly hypocellular with proportion of blasts \<5%, including the erythroid cell count (and including promonocytes in case of M5), no Auer rods, no extramedullary leukemia, neutrophils and platelets rising. The persistence of minimal residual disease in immunophenotypic study will not invalidate the standard cytogenetic complete remission.

Hematological toxicity, hepatic and gastrointestinal toxicity, fever and infections, pulmonary complications, duration of hospitalization

all deaths occurring after the first administration of MylotargTM until the time of transplantation with no leukemic relapse has occurred, and all deaths in the 6 first months after administration of the second dose of MylotargTM with no leukemic relapse occurred.

Rate of patients with capacity to obtain hematopoietic progenitor cells (HPC) for autotransplantation. This analysis has not been performed, because data were not available in sites.

Rate of patients that have relapse after 6 months of obtained complete remission.

rate of patients alive within 6 months of obtained complete remission

Grupo Cooperativo de Estudio y Tratamiento de las Leucemias Agudas y Mielodisplasias

Idarubicin, cytarabine, Mylotarg, G-CSF.

Mylotarg: Cohort 1 (20 evaluable patients):

GO: 3 mg/m\^2 (maximum 5 mg), IV infusion, 2 hours, day 1. Idarubicin: 12 mg/m\^2, IV, 30 minutes, on days 2, 3, 4. Cytarabine (cytosine arabinoside): 100 mg/m\^2 IV continuous infusion on days 1 to 7, to begin 4 hours after the administration of GO.

Cohort 1

Cohort 2 (20 evaluable patients):

G-CSF: 150 mcg/m\^2, SC, days 0 to 7, to begin 12 to 18 hours before treatment with Gemtuzumab. GO: 3 mg/m\^2 (maximum 5 mg), IV infusion, 2 hours, day 1.

Idarubicin: 12 mg/m\^2, IV, 30 minutes, on days 2, 3, 4. Cytarabine (cytosine arabinoside): 100 mg/m\^2 IV continuous infusion on days 1 to 7, to begin 4 hours later after the administration of GO.

Cohort 2

Idarubicin, cytarabine, Mylotarg, G-CSF.

Mylotarg::

GO: 5 mg/m\^2 (maximum 10 mg), IV infusion, 2 hours, day 1. If no adequate response, GO: 3 mg/m\^2 (maximum 5 mg), IV infusion, 2 hours, day 1.

Idarubicin: 12 mg/m\^2, IV, 30 minutes, on days 2, 3, 4. Cytarabine (cytosine arabinoside): 100 mg/m\^2 IV continuous infusion on days 1 to 7, to begin 4 hours after the administration of GO.

5 Patients Treated in Trial With Prrotocol Version 1.0

Mylotarg: Cohort 1 version 1.0 (5 evaluable patients):

GO: 6 mg/m\^2 (maximum 10 mg), IV infusion, 2 hours, day 1. Idarubicin: 12 mg/m\^2, IV, 30 minutes, on days 2, 3, 4. Cytarabine (cytosine arabinoside): 100 mg/m\^2 IV continuous infusion on days 1 to 7, to begin 4 hours after the administration of GO.

If chemo-sensitivity is observed after a first course of treatment (50% or more reduction of blasts compared to baseline) a second identical cycle will be administered.

Cohort 1, Version 1.0

Mylotarg: Cohort 1 (20 evaluable patients):

GO: 3 mg/m\^2 (maximum 5 mg), IV infusion, 2 hours, day 1. Idarubicin: 12 mg/m\^2, IV, 30 minutes, on days 2, 3, 4.

Cytarabine (cytosine arabinoside): 100 mg/m\^2 IV continuous infusion on days 1 to 7, to begin 4 hours after the administration of GO.

Cohort 1, Version 2.0

Total

Age, Continuous

The first 5 patients received GO 6mg/m2 but this dose was halted by unacceptable toxicity. Therefore, in Cohort 1 were included 20 patients receiving IA plus 3 mg/m2 GO. Cohort 2 included 20 patients who received treatment as in cohort 1 plus G-CSF priming

Sex: Female, Male

Spain

One patient has not been evaluated because has not received study treatment.

Region of Enrollment

The first 5 patients received GO 6mg/m2 but this dose was halted by unacceptable toxicity. Therefore, in Cohort 1 were included 20 patients receiving IA plus 3 mg/m2 GO. Cohort 2 included 20 patients who received treatment as in cohort 1 plus G-CSF priming.

Leucocites at diagnosis

1 patient not evaluable because has not received study treatment.

Citogenetic

From cohort 1 version 1.0, one patient did not receive any study treatment (PIS withdrawal), for that reason is not considered for outcome assessment.

Dr. Jordi Sierra

Mylotarg: Cohort 1 (20 evaluable patients):

GO: 3 mg/m\^2 (maximum 5 mg), IV infusion, 2 hours, day 1. Idarubicin: 12 mg/m\^2, IV, 30 minutes, on days 2, 3, 4. Cytarabine (cytosine arabinoside): 100 mg/m\^2 IV continuous infusion on days 1 to 7, to begin 4 hours after the administration of GO.

Initial 5 patients included in cohort 1 version 1.0 (closed due toxicity) have been evaluated for safety outcome but not evaluated for efficacy because the treatment is not feasible.

Complete Remission of the Disease

Grade IV Hematologic toxicity

Grade II Hematologic toxicity

Grade I/II Hepatic toxicity

Grade III/IV hepatic toxicity

Grade I/II Infection

Grade III/IV Infection

Initial 5 patients of cohort 1 (closed due toxicity)

Idarubicin, cytarabine, Mylotarg

Mylotarg: Cohort 1 (20 evaluable patients):

GO: 3 mg/m\^2 (maximum 5 mg), IV infusion, 2 hours, day 1. Idarubicin: 12 mg/m\^2, IV, 30 minutes, on days 2, 3, 4. Cytarabine (cytosine arabinoside): 100 mg/m\^2 IV continuous infusion on days 1 to 7, to begin 4 hours after the administration of GO.

Secondary Toxicity to Mylotarg(R)

Cohort 1 Version 2.0

Mortality at Induction

Initial 5 patients included in cohort 1 version 1.0 (closed due toxicity) have been evaluated for safety outcome but not evaluated for efficacy because the treatment is not feasible. This analysis has not been performed because data were not available for any of the cohorts studied.

Capacity to Obtain Hematopoietic Progenitor Cells (HPC) for Autotransplantation - DATA NOT COLLECTED

Idarubicin, cytarabine, Mylotarg.

Mylotarg: Cohort 1 (20 evaluable patients):

GO: 3 mg/m\^2 (maximum 5 mg), IV infusion, 2 hours, day 1. Idarubicin: 12 mg/m\^2, IV, 30 minutes, on days 2, 3, 4. Cytarabine (cytosine arabinoside): 100 mg/m\^2 IV continuous infusion on days 1 to 7, to begin 4 hours after the administration of GO.

Spots Global Cancer Trial Database for novo acute myeloid leukemia