Disrupting the Bone Marrow Microenvironment With G-CSF in Acute Lymphoblastic Leukemia

A Pilot Study of G-CSF to Disrupt the Bone Marrow Microenvironment in Relapsed or Refractory Acute Lymphoblastic Leukemia

The purpose of this study is to determine the ability of G-CSF to disrupt the bone marrow microenvironment as a means to increase the efficacy of chemotherapy in patients with relapsed or refractory acute lymphoblastic leukemia (ALL).

Study Overview

• Status: Completed
• Conditions: Precursor Cell Lymphoblastic Leukemia-Lymphoma
• Intervention / Treatment: Drug: Dexamethasone; Drug: G-CSF; Drug: Ifosfamide; Drug: Etoposide; Drug: Mesna

Detailed Description

In this study, we will combine G-CSF as priming prior to and during the administration of salvage chemotherapy regimen in ALL. Abundant data suggests that leukemic cells receive key growth and survival signals from the bone marrow microenvironment. Our preclinical data show that 4-5 days of G-CSF treatment is associated with a loss of osteoblasts and decreases expression of key chemokine/ cytokines which support lymphocyte development. The investigators hypothesize that G-CSF will disrupt the protective effects of the bone marrow microenvironment and augment the effect of chemotherapy in adults with ALL. This is a pilot study of G-CSF priming in adult patients with relapsed or refractory ALL to determine the feasibility and to characterize the effect of G-CSF treatment on the marrow microenvironment.

• Study Type: Interventional
• Enrollment (Actual): 13
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago Medical Center
  • Missouri
    • St. Louis, Missouri, United States, 63110
      • Washington University School of Medicine

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

Inclusion Criteria:

• Acute lymphoblastic leukemia diagnosed according to WHO criteria (>25% lymphoblasts in BM) which is relapsed or refractory to therapy. Patients with t(9;22) must be refractory to BCR-ABL tyrosine kinase inhibitors.
• Age ≥ 18 years
• ECOG performance status ≤ 3.

• Adequate organ function defined as:

  • Calculated creatinine clearance ≥ 50 ml/min
  • AST, ALT, total bilirubin ≤ 2 x institutional ULN except when in the opinion of treating physician elevated levels are due to direct involvement of leukemia (eg. hepatic infiltration or biliary obstruction due to leukemia)
• Women of childbearing potential and sexually active males must be willing and able to use effective contraception while on study.
• Able to provide signed informed consent prior to registration on study.

Exclusion Criteria:

• Previous salvage chemotherapy with ifosfamide and etoposide
• Pregnant or nursing
• Received any other investigational agent or cytotoxic chemotherapy within the preceding 2 weeks
• Received colony stimulating factors filgrastim or sargramostim within 1 week or pegfilgrastim within 2 weeks of study
• Severe concurrent illness that would limit compliance with study requirements

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: G-CSF + Ifosfamide + Etoposide + Dexamethasone + Mesna; G-CSF = 10 mcg/kg/d SQ starting on day 1 and continuing until ANC >=1000/mcL x 2 days Ifosfamide = 3330 mg/m2/d CIVI over 24 hours on Days 4-6 Etoposide = 150 mg/m2 IV over 2 hours BID on Days 4-6 Dexamethasone = 5 mg/m2 PO or IV BID on Days 4-10 Mesna = 2660 mg/m2/d continuous IV infusion over 24 hours on Days 4-6. 2000 mg/m2 continuous IV infusion over 12 hours on Day 7 to be started immediately after completion of ifosfamide.

Drug: Dexamethasone; Other Names: Decadron; Drug: G-CSF; Other Names: Filgrastim; Granulocyte Colony-Stimulating Factor; Neupogen; Recombinant Methionyl Human G-CSF; Drug: Ifosfamide; Other Names: Ifex; Isophosphamide; Drug: Etoposide; Other Names: VP-16; Etopophos; Drug: Mesna; Other Names: Mesnex

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment-related mortality		30 days after start of treatment
Delayed hematologic recovery	Defined as neutrophil recovery (ANC > 1,000/mm3) > 42 days after the start of chemotherapy in the absence of persistent leukemia	Day 46 of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete remission rate cytogenetic complete remission		42 days
Overall survival	Every 6 months	2 years
Disease-free survival	Every 6 months	2 years
Remission duration	Every 6 months	2 years
Frequency and severity of adverse events		30 days post treatment
Interaction of pretreatment disease and patient characteristics on clinical outcomes	Morphology, cytogenetics, immunophenotype, WBC, and performance status	Baseline

Collaborators and Investigators

• Sponsor: Washington University School of Medicine

Publications and helpful links

Helpful Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

Study record dates

Study Major Dates

• Study Start: July 1, 2011
• Primary Completion (Actual): October 1, 2014
• Study Completion (Actual): November 1, 2015

Study Registration Dates

• First Submitted: March 31, 2011
• First Submitted That Met QC Criteria: April 6, 2011
• First Posted (Estimate): April 8, 2011

Study Record Updates

• Last Update Posted (Estimate): September 20, 2016
• Last Update Submitted That Met QC Criteria: September 19, 2016
• Last Verified: September 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antineoplastic Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Alkylating; Alkylating Agents; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Adjuvants, Immunologic; Dexamethasone; Etoposide; Ifosfamide; Lenograstim
• Other Study ID Numbers: 201104323