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Total Marrow Irradiation and Myeloablative Chemotherapy Followed By Double Umbilical Cord Blood Transplantation In Patients With High Risk Hematological Malignancies

Phase 1
45 Years
Open (Enrolling)
Leukemia, Myelodysplastic Syndrome

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Trial Information

Total Marrow Irradiation and Myeloablative Chemotherapy Followed By Double Umbilical Cord Blood Transplantation In Patients With High Risk Hematological Malignancies



- Determine the maximum tolerated dose of total marrow irradiation (TMI) delivered by
image-guided tomographic intensity-modulated radiotherapy when administered in
combination with myeloablative chemotherapy in patients undergoing double umbilical
cord blood (UCB) transplantation for refractory acute leukemia.


- Determine the incidence of engraftment (defined as achievement of neutrophil count >
500/uL at 42 days after transplantation).

- Determine the incidence of platelet engraftment at 6 months and at 1 year after

- Evaluate the incidence of complete donor chimerism and the relative contribution of
each UCB unit to donor engraftment within the first 100 days after transplantation.

- Determine the incidence of transplantation-related mortality (TRM) at 6 months after
treatment with a TMI-containing myeloablative conditioning regimen.

- Determine the incidence of grade II-IV and grade III-IV acute graft-versus-host disease
(GVHD) at 100 days after transplantation.

- Determine the incidence of chronic GVHD at 1 year after transplantation.

- Determine the incidence of relapse at 1 year after transplantation.

- Determine the survival and disease-free survival at 1 and 2 years after

- Assess the durability of remission based on presence of rapid early response (defined
by clearance of leukemic blasts from the bone marrow at 21 days after transplantation).

OUTLINE: This is a dose-escalation study of total marrow irradiation (TMI).

- Myeloablative conditioning regimen: Patients receive fludarabine phosphate IV over 1
hour once daily for 3 days between days -12 and -6 and cyclophosphamide IV once daily
for 2 days between days -11 and -6. Patients undergo TMI once daily for 4-8 days
between days -8 and -1.

- Donor umbilical cord blood (UCB) transplantation: Patients undergo single-unit or
double-unit donor UCB transplantation on day 0. Patients receive filgrastim (G-CSF) IV
or subcutaneously once daily beginning on day 1 and continuing until blood counts

- Graft-versus-host disease (GVHD) prophylaxis: Patients receive cyclosporine IV over 2
hours or orally 2-3 times daily beginning on day -3 and continuing until day 100,
followed by a taper until day 180, in the absence of GVHD. Patients also receive
mycophenolate mofetil IV or orally 2-3 times daily beginning on day -3 and continuing
until day 30 (or 7 days after engraftment), in the absence of acute GVHD.

Patients are followed periodically for up to 2 years after transplantation.

Inclusion Criteria:

- Acute lymphoblastic leukemia

- ≥ Complete remission 2 (CR2) (adults ≥ 18 years)

- CR2 in pediatrics (defined as <18 years) and <12 months duration of first

- ≥ CR3 or not in remission (pediatric patients <18 years)

- T cell leukemia ≥ CR2

- Myelodysplastic syndrome

- ≤ 55 years of age and ≥ 10% blasts, not responsive to hypomethylating agents
and/or conventional therapy

- Acute myeloid leukemia

- Not in remission (pediatric patients <18 years)

- Not in remission (10-30% blasts in the bone marrow for adult patients ≥18 years
and ≤ 45 years)

- Patients with prior CNS involvement are eligible provided that it has been treated
and is in remission. CNS therapy (chemotherapy or radiation) should continue as
medically indicated during the protocol.

- Have acceptable organ function within 14 days of study registration defined as:

- Renal: glomerular filtration rate > 60ml/min/1.73m2

- Hepatic: bilirubin, aspartate aminotransferase (AST), alanine aminotransferase
(ALT), Alkaline phosphatase (ALP) < 5 x upper limit of normal (ULN)

- Pulmonary function: Carbon Monoxide Diffusing Capacity corrected (DLCOcorr) >
50% of normal, (oxygen saturation [>92%] can be used in child where pulmonary
function tests (PFT's) cannot be obtained)

- Cardiac: left ventricular ejection fraction ≥ 45% by echocardiogram (ECHO) or
multi gated acquisition scan (MUGA)

- Karnofsky performance status (PS) >80% for ages 16 years and older or Lansky Play
Score >50

- Women of childbearing potential must agree to use adequate contraception (diaphragm,
birth control pills, injections, intrauterine device [IUD], surgical sterilization,
subcutaneous implants, or abstinence, etc.) for the duration of treatment.

- Voluntary written consent

Exclusion Criteria:

- Active uncontrolled infection at time of enrollment or documented fungal infection
within 3 months.

- Evidence of Human immunodeficiency virus (HIV) infection

- Pregnant or breast feeding. The agents used in this study may be teratogenic to a
fetus and there is no information on the excretion of agents into breast milk. All
females of childbearing potential must have a blood test or urine study within 2
weeks prior to registration to rule out pregnancy.

- Prior myeloablative transplant within the last 6 months

- Prior total body irradiation (TBI) making total marrow irradiation (TMI) not feasible

Type of Study:


Study Design:

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

Outcome Measure:

Maximum tolerated dose (MTD) of total marrow irradiation (TMI)

Outcome Description:

Maximum tolerated dose (MTD) is the highest dose of a drug or treatment that does not cause unacceptable side effects. The MTD of TMI will be determined by using the modified Continual Reassessment Method (CRM). The goal of this CRM will be to identify 1 of the 5 dose levels which corresponds to the desired maximum toxicity rate of <=15%.

Outcome Time Frame:

Day 100

Safety Issue:


Principal Investigator

Michael R. Verneris, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Masonic Cancer Center, University of Minnesota


United States: Food and Drug Administration

Study ID:




Start Date:

September 2007

Completion Date:

September 2017

Related Keywords:

  • Leukemia
  • Myelodysplastic Syndrome
  • recurrent adult acute lymphoblastic leukemia
  • recurrent childhood acute lymphoblastic leukemia
  • recurrent adult acute myeloid leukemia
  • recurrent childhood acute myeloid leukemia
  • adult acute myeloid leukemia with 11q23 (MLL) abnormalities
  • adult acute myeloid leukemia with inv(16)(p13;q22)
  • adult acute myeloid leukemia with t(15;17)(q22;q12)
  • adult acute myeloid leukemia with t(16;16)(p13;q22)
  • adult acute myeloid leukemia with t(8;21)(q22;q22)
  • Leukemia
  • Myelodysplastic Syndromes
  • Preleukemia
  • Hematologic Neoplasms



Masonic Cancer Center at University of Minnesota Minneapolis, Minnesota  55455