Novo Acute Myeloid Leukemia
Conditions
Brief summary
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.
Interventions
DRUGMylotarg
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.
Sponsors
Grupo Cooperativo de Estudio y Tratamiento de las Leucemias Agudas y Mielodisplasias
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Patients with primary or de novo AML, different than promyelocytic or M3 subtype. 2. Age 18 to 70 years. 3. Written informed consent form
Exclusion criteria
1. Acute leukemia appeared after a myeloproliferative process or a myelodysplastic syndrome longer than 6 months, AML arising after another cured malignant disease (e.g. Hodgkin's disease), and secondary AML treated with alkylating agents or radiation. 2. Acute promyelocytic leukemia. 3. Relevant history of liver disease. Significant impaired liver function (bilirubin, AST or ALT ≥ 2.5 times the normal value) not attributable to leukemic infiltration. 4. Patients with prior heart failure. 5. Symptomatic chronic respiratory failure. 6. Positive serology for HIV, hepatitis C virus or its surface antigen. 7. Estimated life expectancy less than 3 months, despite treatment. 8. Pregnancy or breastfeeding at the time of inclusion in the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Complete Remission of the Disease | 28 days after chemotherapy | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Secondary Toxicity to Mylotarg(R) | Baseline, weekly during treatment and at month 3 and month 6 after first induction. | Hematological toxicity, hepatic and gastrointestinal toxicity, fever and infections, pulmonary complications, duration of hospitalization |
| Mortality at Induction | Weekly during treatment, at third month and at 6 months after last administration of Mylotarg | 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. |
| Capacity to Obtain Hematopoietic Progenitor Cells (HPC) for Autotransplantation - DATA NOT COLLECTED | One month before transplant, expected at 9 months after end of treatment. | 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. |
| Relapse After 6 Months | 6 months from complete remission | Rate of patients that have relapse after 6 months of obtained complete remission. |
| Survival After 6 Months | 6 months after complete remission | rate of patients alive within 6 months of obtained complete remission |
Countries
Spain
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1, 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. | 5 |
| Cohort 1, Version 2.0 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. | 20 |
| Cohort 2 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. | 20 |
| Total | 45 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Cohort 1, Version 1.0 | Cohort 1, Version 2.0 | Cohort 2 | Total |
|---|---|---|---|---|
| Age, Continuous | 56 years | 49 years | 61 years | 61 years |
| Citogenetic Adverse | 1 Participants | 2 Participants | 5 Participants | 8 Participants |
| Citogenetic Favorable | 1 Participants | 5 Participants | 3 Participants | 9 Participants |
| Citogenetic Intermediate | 3 Participants | 13 Participants | 12 Participants | 28 Participants |
| Leucocites at diagnosis | 13.48 Cells x 10^9/L | 7.66 Cells x 10^9/L | 6.96 Cells x 10^9/L | 6.96 Cells x 10^9/L |
| Region of Enrollment Spain | 5 participants | 20 participants | 20 participants | 45 participants |
| Sex: Female, Male Female | 2 Participants | 9 Participants | 5 Participants | 16 Participants |
| Sex: Female, Male Male | 3 Participants | 11 Participants | 15 Participants | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 20 | 2 / 20 | 1 / 5 |
| other Total, other adverse events | 20 / 20 | 19 / 20 | 3 / 5 |
| serious Total, serious adverse events | 3 / 20 | 6 / 20 | 2 / 5 |
Outcome results
Primary
Complete Remission of the Disease
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.
Time frame: 28 days after chemotherapy
Population: 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.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1, Version 1.0 | Complete Remission of the Disease | Partial Response | NA Participants |
| Cohort 1, Version 1.0 | Complete Remission of the Disease | Complete Response | NA Participants |
| Cohort 1, Version 1.0 | Complete Remission of the Disease | Refractory | NA Participants |
| Cohort 1, Version 2.0 | Complete Remission of the Disease | Partial Response | 1 Participants |
| Cohort 1, Version 2.0 | Complete Remission of the Disease | Complete Response | 18 Participants |
| Cohort 1, Version 2.0 | Complete Remission of the Disease | Refractory | 1 Participants |
| Cohort 2 | Complete Remission of the Disease | Complete Response | 16 Participants |
| Cohort 2 | Complete Remission of the Disease | Refractory | 2 Participants |
| Cohort 2 | Complete Remission of the Disease | Partial Response | 2 Participants |
Secondary
Capacity to Obtain Hematopoietic Progenitor Cells (HPC) for Autotransplantation - DATA NOT COLLECTED
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.
Time frame: One month before transplant, expected at 9 months after end of treatment.
Population: 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.
Secondary
Mortality at Induction
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.
Time frame: Weekly during treatment, at third month and at 6 months after last administration of Mylotarg
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1, Version 1.0 | Mortality at Induction | 1 Participants |
| Cohort 1, Version 2.0 | Mortality at Induction | 0 Participants |
| Cohort 2 | Mortality at Induction | 2 Participants |
Secondary
Relapse After 6 Months
Rate of patients that have relapse after 6 months of obtained complete remission.
Time frame: 6 months from complete remission
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1, Version 1.0 | Relapse After 6 Months | 30 percentage of participants |
| Cohort 1, Version 2.0 | Relapse After 6 Months | 59 percentage of participants |
Secondary
Secondary Toxicity to Mylotarg(R)
Hematological toxicity, hepatic and gastrointestinal toxicity, fever and infections, pulmonary complications, duration of hospitalization
Time frame: Baseline, weekly during treatment and at month 3 and month 6 after first induction.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1, Version 1.0 | Secondary Toxicity to Mylotarg(R) | Grade III/IV Infection | 0 percentage of participants |
| Cohort 1, Version 1.0 | Secondary Toxicity to Mylotarg(R) | Grade I/II Hepatic toxicity | 20 percentage of participants |
| Cohort 1, Version 1.0 | Secondary Toxicity to Mylotarg(R) | Grade I/II Infection | 0 percentage of participants |
| Cohort 1, Version 1.0 | Secondary Toxicity to Mylotarg(R) | Grade IV Hematologic toxicity | 0 percentage of participants |
| Cohort 1, Version 1.0 | Secondary Toxicity to Mylotarg(R) | Grade III/IV hepatic toxicity | 40 percentage of participants |
| Cohort 1, Version 1.0 | Secondary Toxicity to Mylotarg(R) | Grade II Hematologic toxicity | 0 percentage of participants |
| Cohort 1, Version 2.0 | Secondary Toxicity to Mylotarg(R) | Grade III/IV hepatic toxicity | 5 percentage of participants |
| Cohort 1, Version 2.0 | Secondary Toxicity to Mylotarg(R) | Grade I/II Infection | 10 percentage of participants |
| Cohort 1, Version 2.0 | Secondary Toxicity to Mylotarg(R) | Grade II Hematologic toxicity | 0 percentage of participants |
| Cohort 1, Version 2.0 | Secondary Toxicity to Mylotarg(R) | Grade III/IV Infection | 5 percentage of participants |
| Cohort 1, Version 2.0 | Secondary Toxicity to Mylotarg(R) | Grade IV Hematologic toxicity | 100 percentage of participants |
| Cohort 1, Version 2.0 | Secondary Toxicity to Mylotarg(R) | Grade I/II Hepatic toxicity | 10 percentage of participants |
| Cohort 2 | Secondary Toxicity to Mylotarg(R) | Grade I/II Hepatic toxicity | 10 percentage of participants |
| Cohort 2 | Secondary Toxicity to Mylotarg(R) | Grade IV Hematologic toxicity | 95 percentage of participants |
| Cohort 2 | Secondary Toxicity to Mylotarg(R) | Grade II Hematologic toxicity | 5 percentage of participants |
| Cohort 2 | Secondary Toxicity to Mylotarg(R) | Grade III/IV Infection | 30 percentage of participants |
| Cohort 2 | Secondary Toxicity to Mylotarg(R) | Grade III/IV hepatic toxicity | 15 percentage of participants |
| Cohort 2 | Secondary Toxicity to Mylotarg(R) | Grade I/II Infection | 25 percentage of participants |
Secondary
Survival After 6 Months
rate of patients alive within 6 months of obtained complete remission
Time frame: 6 months after complete remission
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1, Version 1.0 | Survival After 6 Months | 80 percentage of participants |
| Cohort 1, Version 2.0 | Survival After 6 Months | 80 percentage of participants |