Study of Molecular and Genetic Abnormalities in Patients With Myeloid Neoplasms

Evaluation of the Incidence and Prognostic Impact of Molecular and Genetic Abnormalities in Patients With Acute Myeloid Leukemia, Myelodysplastic Syndrome and Myeloproliferative Neoplasms

The objective of this study is to describe the prevalence and prognostic impact of the most common genetic abnormalities in patients with Myeloid Neoplasms, including Acute Myeloid Leukemia (AML), Myeloproliferative Neoplasms (MPN), Myelodysplastic Syndromes (MDS) and Myeloproliferative/Myelodysplastic Neoplasms. Patients will have samples of blood and/or bone marrow collected and sent to Hospital Israelita Albert Einstein for analysis and storage.

Patients with a diagnosis of Acute Myeloid Leukemia will be treated according to an uniform protocol.

Study Overview

• Status: Completed
• Conditions: Acute Myeloid Leukemia; Myelodysplastic Syndromes; Myeloproliferative Neoplasms; Myeloproliferative/Myelodysplastic Neoplasm
• Intervention / Treatment: Drug: Induction Chemotherapy; Drug: Consolidation Chemotherapy; Drug: Autologous Stem Cell Transplantation; Drug: Allogeneic Stem Cell Transplantation; Drug: Low Dose Cytarabine; Drug: Decitabine

• Study Type: Interventional
• Enrollment (Actual): 455
• Phase: Phase 2

Contacts and Locations

Study Locations

• Brazil
  • SP
    • Sao Paulo, SP, Brazil, 05651901
      • Hospital Israelita Albert Einstein

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Acute Myeloid Leukemia-Intensive Chemotherapy

Inclusion Criteria:

• Diagnosis of AML according to WHO criteria
• Age greater than 18 years
• Performance status (ECOG) between 0-2
• Adequate liver and kidney function
• Signed Informed Consent form
• No prior therapy for AML, except use of hydroxyurea for control of elevated white blood cell counts
• Adequate contraception for fertile men and women
• Eligible for intensive chemotherapy (as judged by the treating physician)

Exclusion Criteria:

• Acute myeloid leukemia with retinoic acid receptor alpha (RARA) translocations (APL, acute promyelocytic leukemia)
• Pregnant women
• HIV-positivity
• New York Heart Association class III and IV congestive heart failure
• Patient refuses to use adequate contraception
• History of hypersensibility to any of the used chemotherapy drugs
• Patient refuses to sign informed consent form

Acute Myeloid Leukemia-Non-Intensive Chemotherapy

Inclusion Criteria:

• Diagnosis of AML according to WHO criteria
• Age greater than 18 years
• Signed Informed Consent form
• No prior therapy for AML, except use of hydroxyurea for control of elevated white blood cell counts
• Adequate contraception for fertile men and women
• Non-eligible for intensive chemotherapy (as judged by the treating physician)

Exclusion Criteria:

• Acute myeloid leukemia with RARA translocations (APL, acute promyelocytic leukemia)
• Pregnant women
• HIV-positivity
• Patient refuses to use adequate contraception
• History of hypersensibility to any of the used chemotherapy drugs
• Patient refuses to sign informed consent form

Chronic Myeloid Disorders:

Inclusion Criteria:

• Diagnosis of Myeloproliferative Neoplasm or Myelodysplastic Syndrome or Myeloproliferative/Myelodysplastic Neoplasm according to WHO criteria
• Age greater than 18 years
• Signed Informed Consent form

Exclusion Criteria:

• Patient refuses to sign informed consent form

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: AML-Intensive Chemotherapy; Patients with Acute Myeloid Leukemia fit for intensive chemotherapy Patients will receive Induction Chemotherapy, and CR will be evaluated after 28 days. Patients who achieve CR post-induction chemotherapy will receive post-remission therapy according to risk: Low risk patients: Consolidation chemotherapy or Autologous stem cell transplantation; Intermediate and high-risk patients: Allogeneic stem cell transplantation Patients who do not achieve CR may receive one second induction cycle, and if CR is achieved may proceed to post-remission therapy as per above. Patients who do not achieve CR after two cycles of induction will be deemed refractory and removed from the study.	Drug: Induction Chemotherapy; Induction chemotherapy for patients with AML eligible for intensive chemotherapy: Cytarabine 200 mg/m2 IV continuous infusion days 1-7; Daunorubicin 90 mg/m2 intravenous piggyback days 1-3; Other Names: Ara-C; Anthracycline; 7+3; Daunorubicin; 3+7; Drug: Consolidation Chemotherapy; Consolidation chemotherapy for patients eligible for intensive chemotherapy with low-risk AML or patients with intermediate-/high-risk AML who do not have matched donors: -Cytarabine 1.5 g/m2 IV in 3 hours days 1, 3 and 5 for 3 cycles; Other Names: Ara-C; Cytarabine; Drug: Autologous Stem Cell Transplantation; Autologous Stem Cell Transplantation for consolidation of patients eligible for intensive chemotherapy with low-risk AML or patients with intermediate-/high-risk AML who do not have matched donors: Busulfan 1 mg/Kg PO q6h or 130 mg/m2 IV once daily days -7 to -4; Cyclophosphamide 60 mg/Kg IV once daily days -3 and -2; Other Names: ASCT; ABMT; Autologous Bone Marrow Transplantation; Drug: Allogeneic Stem Cell Transplantation; Allogeneic Stem Cell Transplantation for consolidation of patients eligible for intensive chemotherapy with intermediate-/high-risk AML Conditioning regimen: Busulfan 1 mg/Kg PO q6h or 130 mg/m2 IV once daily days -7 to -4; Cyclophosphamide 60 mg/Kg IV once daily days -3 and -2 or Fludarabine 40 mg/m2 IV once daily days -7 to -4; Other Names: AlloSCT; Allogeneic Bone Marrow Transplantation
Other: AML-Non-intensive chemotherapy; Patients with acute myeloid leukemia not fit for intensive chemotherapy Patients will receive induction chemotherapy with either low dose cytarabine or decitabine. Assignment to each drug will depend on drug availability and physician discretion. No randomization will be done between the drugs. Cycles will be repeated every 28 days. Patients who achieve CR will continue to post-consolidation therapy with either cytarabine or decitabine, based on the induction therapy received. Patients will receive a maximum of 4 cycles until achieving CR, if no response is seen after 4 cycles patients will be deemed refractory.	Drug: Low Dose Cytarabine; Chemotherapy for patients with AML who are not fit for intensive chemotherapy: Cytarabine 60 mg/m2 subcutaneous (SQ) bid days 1-5 (until CR or maximum 4 cycles); Cytarabine 40 mg/m2 SQ bid days 1-5 (after CR, until a maximum of 3 years of therapy or relapse, whichever comes first); Other Names: Low dose ara-C; LDAC; Drug: Decitabine; Chemotherapy for patients with AML who are not fit for intensive chemotherapy: Decitabine 20 mg/m2 IV once daily days 1-10 (until CR or maximum 4 cycles); Decitabine 20 mg/m2 IV once daily days 1-5 (after CR, until a maximum of 3 years of therapy or relapse, whichever comes first); Other Names: Dacogen; DAC; 2-aza-5´-deoxycytidine
No Intervention: Chronic Myeloid Disorders; Patients with Chronic Myeloid Disorders: Myeloproliferative Neoplasms; Myelodysplastic Syndromes; Myeloproliferative/Myelodysplastic Neoplasms

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Prevalence of molecular and cytogenetic abnormalities	As assessed by results of molecular and cytogenetic tests and frequency in the population studied	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival	Evaluation of 5-years overall survival in patients with Acute Myeloid Leukemia, Myeloproliferative Neoplasms, Myelodysplastic Syndromes and Myeloproliferative/Myelodysplastic Neoplasms	5 years
Response rate	Evaluate complete remission (CR) rate at 1 month for patients with Acute Myeloid Leukemia who received induction chemotherapy. Complete remission was defined by the presence of < 5% blasts in the bone marrow (BM) with > 1 x 10^9/L neutrophils and >100x10^9/L platelets in the peripheral blood (PB)	1 month
Disease Free Survival	Evaluate rate of 5-years disease-free survival in patients with Acute Myeloid Leukemia who enter complete remission after induction chemotherapy	5 years
Cumulative incidence of relapse and non-relapse mortality	Evaluate 5-years cumulative incidence of relapse and non-relapse mortality in patients with Acute Myeloid Leukemia who achieve complete remission following induction chemotherapy	5 years
Number of participants with adverse events as a measure of safety and tolerability	Evaluate hematological and non-hematological toxicity in patients with Acute Myeloid Leukemia treated according to the protocol. Toxicity will be graded as per the National Cancer Institute Common Toxicity Criteria for Adverse Events v4.0.3	1 year
Cumulative Incidence of Transformation to Acute Myeloid Leukemia	Evaluate 5-years incidence of transformation to Acute Myeloid Leukemia in patients with Myeloproliferative Neoplasms, Myelodysplastic Syndromes and Myeloproliferative/Myelodysplastic Neoplasms	5 years

Collaborators and Investigators

• Sponsor: Hospital Israelita Albert Einstein
• Investigators: Study Director: Fabio P Santos, MD, Hospital Israelita Albert Einstein; Study Chair: Nelson Hamerschlak, MD, PhD, Hospital Israelita Albert Einstein

Study record dates

Study Major Dates

• Study Start: October 1, 2012
• Primary Completion (Actual): December 1, 2014
• Study Completion (Actual): November 1, 2016

Study Registration Dates

• First Submitted: January 2, 2013
• First Submitted That Met QC Criteria: March 10, 2014
• First Posted (Estimate): March 12, 2014

Study Record Updates

• Last Update Posted (Estimate): November 8, 2016
• Last Update Submitted That Met QC Criteria: November 7, 2016
• Last Verified: November 1, 2016

More Information

Terms related to this study

• Keywords: Acute Myeloid Leukemia; MPN; Myeloproliferative Neoplasms; AML; Leukemia; MDS; Myelodysplastic Syndromes; Chronic myelomonocytic leukemia (CMML); Myeloproliferative/Myelodysplastic Neoplasm; Polycythemia Vera (PV); Essential Thrombocythemia (ET); Myelofibrosis (MF)
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Disease; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Neoplasms; Syndrome; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Myeloproliferative Disorders; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Decitabine; Cytarabine; Daunorubicin
• Other Study ID Numbers: LMA Brasil; 11/1714 (Other Identifier: HIAE CEP)