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A Trial of Rituximab Combined With Prednisone/Ifosfamide/Etoposide for Relapsed Acute Lymphoblastic Leukemia (ALL)

1 Year
30 Years
Not Enrolling
Leukemia, Acute Lymphoblastic Leukemia, ALL

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Trial Information

A Trial of Rituximab Combined With Prednisone/Ifosfamide/Etoposide for Relapsed Acute Lymphoblastic Leukemia (ALL)

Rationale for study design:

The combination of etoposide and ifosfamide is a reinduction regimen used in many previous
studies for pediatric B lineage acute lymphoblastic leukemia (ALL). It does not use
anthracyclines, and therefore can be safely used in patients at risk for cardiac toxicity
due to previous anthracycline use.

Previous studies in adult patients with ALL have demonstrated safety and efficacy with the
addition of rituximab to other induction regimens. Rituximab is an anti-CD20 monoclonal
antibody. Approximately one-half of pediatric cases of B precursor ALL express the CD20
antigen on the leukemic blasts. The use of rituximab provides a potential target for CD20
positive cells, therefore improving the rates of cytotoxicity associated with the
chemotherapy. Rituximab has been previously utilized in many pediatric and adult regimens
in combination with other chemotherapeutic agents, and is expected to be safe with the
combination of etoposide and ifosfamide. However, since it has never been studied with this
combination of chemotherapy, strict stopping rules are in place to ensure that it is a safe

A recent study demonstrated upregulation of CD20 expression on leukemic blasts exposed to
one week of prednisone therapy. This increase in expression occurred in the majority of
B-ALL patient samples, regardless of whether the patient initially expressed CD20 on the
surface of the leukemic blasts. In those samples with upregulation of CD20 treated with
rituximab, cytotoxicity from rituximab was more successful than in samples with a smaller
percentage of CD20 expression.

Therefore, prednisone will be given for two weeks in combination with etoposide and
ifosfamide. It is hoped that the percentage of leukemic blasts expressing CD20 will
increase with this combination of medications, allowing the rituximab to be more effective
when given weekly starting on day 8 of therapy. To better understand this process, samples
of blood and bone marrow will be collected to quantify CD20 expression and the amount of
leukemia present at multiple time points during the month of study duration.

Inclusion Criteria:

1. Age: Patients must be 1-30 years of age at initial diagnosis.

2. Diagnosis: Patients must have histologically-confirmed relapsed/refractory Acute
Lymphoblastic Leukemia (ALL).

3. Disease Status:Patients must be in

- second or greater bone marrow relapse (≥ 25% blasts by morphology), or

- refractory to reinduction therapy with one or more attempts at remission
reinduction (end of reinduction blasts ≥ 5% by morphology and/or end of
reinduction MRD ≥ 1% by flow cytometry).

- Patients with combined bone marrow and extramedullary relapse are eligible (CNS
3 patients excluded).

4. Performance Status: Patients must have a performance status of ≥50 from the Lansky
Scale if <10 years or ≥ 50 or from the Karnofsky Scale if ≥ 10 years. Patients who
are unable to walk because of paralysis, but who are up in a wheelchair will be
considered ambulatory for the purpose of assessing the performance score.

5. Prior Therapy: Patients must have fully recovered from the acute toxic effects of all
prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study and
meet time restrictions from end of prior therapy as stated below:

- Myelosuppressive chemotherapy: must not have received within 2 weeks of entry
onto this study (4 weeks in the case of nitrosurea containing therapy).
Patients who relapse while receiving ALL maintenance chemotherapy will not be
required to have a waiting period before entry onto this study. Cytoreduction
with hydroxyurea can be initiated and continued for up to 24 hours prior to the
start of therapy.

- XRT: must be ≥ 4 weeks since the completion of radiation therapy.

- Study specific limitations: must be ≥ 7 days since the completion of
corticosteroid therapy.

- Growth factor(s): Must not have received any hematopoietic growth factors (GCSF,
Neulasta, or GMCSF) within 7 days of study entry.

- Stem Cell Transplant: Patients must be at least two months from stem cell
transplant, must be off immunosuppressives, and must have no evidence of active
graft versus host disease.

Biologic (anti-neoplastic agent): At least 7 days since the completion of therapy
with a biologic agent. For agents that have known adverse events occurring beyond 7
days after administration, this period must be extended beyond the time during which
adverse events are known to occur. The duration of this interval must be discussed
with the study chair.

6. Institutional review board approval.

7. Individual informed consent per local guidelines and federal and state regulations.

8. Organ Function: All patients must have adequate organ function defined as:

- Renal Function: Patients must have a calculated creatinine clearance or
radioisotope GFR ≥ 70mL/min/1.73m2 or a normal serum creatinine based on

- Liver Function: Total bilirubin ≤ 1.5 x institutional upper limit of normal
(ULN) for age, AND SGPT (ALT) ≤ 5 x institutional ULN for age

- Cardiac Function: Ejection fraction > 50% on echocardiogram or MUGA Scan, OR
Shortening fraction ≥ 27% on echocardiogram or MUGA Scan

- Reproductive Function: Due to potential teratogenic effects of the drugs, all
post-menarchal female patients must have a negative serum beta HCG prior to
study enrollment. In addition, all patients of childbearing or child-fathering
potential must agree to a medically acceptable form of contraception, including
abstinence, while on study.

Exclusion Criteria:

1. Patients with an active and uncontrolled infection, defined as need for pressors,
and/or positive cultures for 24 hours.

2. Patients recovering from allogeneic bone marrow transplantation who are still on

3. Pregnant or lactating females. Women of childbearing age will agree to use
contraception during the protocol.

4. Patients currently receiving other investigational agents, medications, or
supplements with a known anti-leukemic effect.

5. Patients who, in the opinion of the investigator, will not be able to comply with
safety monitoring requirements of the study.

6. Patients with reactivation of hepatitis B prior to starting therapy.

7. Patients who are HIV positive.

8. Patients must not have CNS 3 involvement.

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

4 month Event Free Survival (EFS)

Outcome Description:

To estimate the 4 month EFS after therapy with rituximab and cytotoxic chemotherapy (prednisone/etoposide/ifosfamide) in patients with second relapse/refractory ALL.

Outcome Time Frame:

one year after enrollment

Safety Issue:


Principal Investigator

Todd Cooper, DO

Investigator Role:

Principal Investigator

Investigator Affiliation:

Emory University/Children's Healthcare of Atlanta


United States: Institutional Review Board

Study ID:




Start Date:

September 2010

Completion Date:

October 2012

Related Keywords:

  • Leukemia
  • Acute Lymphoblastic Leukemia
  • ALL
  • ALL
  • Leukemia
  • Rituximab
  • Pediatrics
  • Leukemia
  • Leukemia, Lymphoid
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma



Emory University Atlanta, Georgia  30322
Children's Healthcare of Atlanta Atlanta, Georgia  30342
The children's Mercy Hospital Kansas City, Missouri  64108