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Busulfan-Fludarabine-Clofarabine With Allogeneic Stem Cell Transplantation for Advanced Refractory Acute Myeloid Leukemia, Myelodysplastic Syndrome, and Advanced, Gleevec Refractory Chronic Myeloid Leukemia. A Randomized Phase II Study.

Phase 2
60 Years
Not Enrolling
Acute Myeloid Leukemia, Myelodysplastic Syndrome, Chronic Myeloid Leukemia

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Trial Information

Busulfan-Fludarabine-Clofarabine With Allogeneic Stem Cell Transplantation for Advanced Refractory Acute Myeloid Leukemia, Myelodysplastic Syndrome, and Advanced, Gleevec Refractory Chronic Myeloid Leukemia. A Randomized Phase II Study.

Busulfan is a chemotherapy drug that kills cancer cells by binding to DNA (the genetic
material of cells). Clofarabine is designed to interfere with the growth and development of
cancer cells. Fludarabine is designed to interfere with DNA repair enzymes so that the
leukemic cells cannot repair damaged DNA. This may increase the likelihood of the cell
dying. These drugs are being given to try to kill cancerous cells and weaken your immune
system in order to lower the risk of stem cell transplant rejection.

If you are found to be eligible to take part in this study, you will be randomly assigned
(as in the toss of a coin) to 1 of 4 study groups. Three (3) of the groups will receive
busulfan, fludarabine, and clofarabine at different dose levels. The 4th group will only
receive busulfan and clofarabine. As the study continues, participants will be assigned
using a method called adaptive randomization. This method works by increasing the chances
of being assigned to the group that has had the best results in the study so far. You will
know which group you have been assigned to.

Participants will receive busulfan, fludarabine, and/or clofarabine once a day for 4 doses.
You will first receive an additional low-level "test" dose of busulfan given by vein to
check how your blood levels change over time. This information will be used to decide the
next dose needed to reach a target blood level of busulfan. You will have a total of about
6 and 1/2 tablespoons of blood drawn over time to check your busulfan blood levels following
one or more of the busulfan treatments. Up to 11 samples of blood will be drawn to check
your blood levels of busulfan during the next 11 hours following the test dose and the first
high-dose busulfan treatment. Each sample will require about 1 teaspoon of blood. A
heparin lock line will be placed in a vein to lower the number of needle sticks needed for
these draws. If it is not possible for these blood level tests to be performed for
technical or scheduling reasons, you will receive the standard fixed (unchanging) dose of

Clofarabine and fludarabine (if applicable) will be given through a central venous catheter
(CVC) over 1 hour, once a day, for 4 days. Busulfan will also be given through the CVC over
3 hours.

If you are going to be receiving a transplant from an HLA-nonidentical or unrelated donor,
you will also receive thymoglobulin (ATG) over 4 hours on the 3 days before the transplant
to further weaken your immune system to reduce the risk of rejecting of the transplant.
After the transplant, you will receive tacrolimus, methotrexate, or other immunosuppressive
(lowering the immune system) drugs in the standard manner to lower the risk of graft-vs-host
disease (GVHD), a reaction of the donor's immune cells against the recipient's body.

The allogeneic stem cells (bone marrow or peripheral blood stem cells) will also be given
through the CVC. You will receive the drug G-CSF (filgrastim) as an injection under the
skin once a day, starting 1 week after the transplant, until your blood cell levels return
to normal.

Patients usually stay in the hospital for about 4 weeks after stem cell transplantation.
After you are released from the hospital, you will continue to be monitored as an outpatient
for infections and transplant-related complications for at least 100 days after the

You will have blood tests (about 4 tablespoons of blood) and bone marrow aspirations
performed at 1, 3, 6, and 12 months after the transplant, to check if the disease is in
remission (has not come back). Your health status will be followed with the help of your
local doctor to find out if the leukemia or MDS comes back, as well as to check the length
of your survival.

This is an investigational study. All of the drugs used in this study are approved by the
FDA for treatment of cancer. Busulfan has been approved for use in stem cell
transplantation. The use of these drugs together with stem cell transplant is experimental.
Up to 70 patients will take part in this study. All will be enrolled at the M. D. Anderson
Cancer Center.

Inclusion Criteria:

1. Diagnosis or 1) Acute myeloid leukemia past first remission, in first or subsequent
relapse, or induction failures, 2) Myelodysplastic syndromes with intermediate or
high risk International Prognostic Scoring System score (IPSS scores) (16), and
having failed previous chemotherapy, or 3) Chronic Myeloid Leukemia,
Philadelphia-chromosome positive and having failed / being resistant to therapy based
on Gleevec or other tyrosine kinase inhibitors.

2. Patient has not been administered intensive systemic chemotherapeutic drugs within 21
days prior to trial enrollment (bone marrow transplant (BMT) Day -9). Gleevec,
alternative tyrosine kinase inhibitors, other nonmyelosuppressive agents, low dose
cytarabine, hydroxyurea is permitted if indicated to control the leukemia. All
tyrosine inhibitor- or other non-myelosuppressive agents have to be terminated at
least one week prior to admission for this treatment.

3. No uncontrolled infection. Protocol principal investigator (PI) will be final arbiter
if there is uncertainty regarding whether a previous infection is resolved on
appropriate antibiotics therapy.

4. age
5. A related or unrelated donor who is HLA-matched or mismatched in 1 HLA, A, B, C, DR
or DQ locus is acceptable (i.e. at least a 9/10 matched related or unrelated donor,
matched with molecular high-resolution technique per current standard for the BMT

6. ZUBROD performance status <2

7. Life expectancy is not severely limited by concomitant illness.

8. Left ventricular ejection fraction >/=45% No uncontrolled arrhythmias or symptomatic
cardiac disease.

9. Forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) and carbon
monoxide diffusing capacity (DLCO) >/= 50% of expected corrected for hemoglobin. In
10. Serum creatinine
11. Serum glutamic pyruvic transaminase (SGPT) alkaline phosphatase within accepted laboratory standard normal limits or considered
not clinically significant. No evidence of chronic active hepatitis or cirrhosis. If
positive hepatitis serology, discuss with Study Chairman and perform liver biopsy
pror to determining study eligibility.

12. Female patient is not pregnant (negative human chorionic gonadotropin (hCG) pregnancy
test in all women of child-bearing-potential in accordance with departmental

13. Patient or patient's legal representative, parent(s) or guardian able to sign
informed consent.

Exclusion Criteria:

1. Effusion or ascites estimated to be >1L prior to drainage.

2. HIV-positive.

3. Hepatitis C or HBsAg positive

4. Prior stem cell transplant after a myeloablative conditioning program (such as
busulfan-based using a total dose of >/= 12 mg/kg given by mouth or >/= 10 mg/kg IV,
or a total-body irradiation-based program.

5. Active or prior Central Nervous System (CNS) leukemia

6. Biphenotypic acute leukemia.

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Optimal Dose Level

Outcome Time Frame:

Four combinations of daily doses to be studied in 4 day schedule

Safety Issue:


Principal Investigator

Richard E. Champlin, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

M.D. Anderson Cancer Center


United States: Institutional Review Board

Study ID:




Start Date:

September 2006

Completion Date:

March 2013

Related Keywords:

  • Acute Myeloid Leukemia
  • Myelodysplastic Syndrome
  • Chronic Myeloid Leukemia
  • Acute Myeloid Leukemia
  • AML
  • Myelodysplastic Syndrome
  • MDS
  • Chronic Myeloid Leukemia
  • CML
  • Busulfan
  • Busulfex
  • Myleran
  • Fludarabine
  • Fludara
  • Fludarabine Phosphate
  • Clofarabine
  • Clofarex
  • Clolar
  • Allogeneic stem cell transplantation
  • ASCT
  • Stem Cell
  • Gleevec
  • Imatinib Mesylate
  • Leukemia
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive
  • Myelodysplastic Syndromes
  • Preleukemia



UT MD Anderson Cancer Center Houston, Texas  77030