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

Study Overview
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Brief Summary
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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).

Detailed Description
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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.

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

Conditions
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Precursor Cell Lymphoblastic Leukemia-Lymphoma

Intervention / Treatment
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* Drug: G-CSF
* Drug: Ifosfamide
* Drug: Etoposide
* Drug: Dexamethasone
* Drug: Mesna


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: G-CSF + Ifosfamide + Etoposide + Dexamethasone + Mesna<br>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: G-CSF<br> <br> * Other names: Recombinant Methionyl Human G-CSF;Drug: Ifosfamide<br> <br> * Other names: Isophosphamide;Drug: Etoposide<br> <br> * Other names: VP-16;Drug: Dexamethasone<br> <br> * Other names: Decadron;Drug: Mesna<br> <br> * Other names: Mesnex;|

What is the study measuring?
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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 |