Total Marrow Irradiation for Refractory Acute Leukemia

OBJECTIVES:

Primary

- 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 or hematopoietic stem cell for refractory acute leukemia.

Secondary

- 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
transplantation.

- 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 transplantation.

- 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
recover.

- Related Donor: Related donor bone marrow will be collected (target cell dose 5x10^8
nucleated cells/kg recipient weight, minimum 3x10^8 nucleated cells/kg recipient weight)
and infused without processing on day 0.

- 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 and ≤ 55 years)

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

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

- T cell leukemia ≥ CR2

- Evidence of pre-transplant minimal residual disease (MRD) by flow cytometry, FISH
or cytogenetics

- 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 ≤ 55 years)

- Evidence of pre-transplant minimal residual disease (MRD) by flow cytometry, FISH
or cytogenetics

- Multiple myeloma

- No prior autologous transplant and fitting into one of the following disease
categories:

- Early disease stage (CR1/PR1) with high-risk molecular features

- Early disease stage (CR1/PR1) with high-risk clinical features

- Late disease stage (CR2/PR2+) with high-risk clinical features

- Other high risk hematologic malignancies - to be approved by 2 or more
hematology/oncology and BMT physicians

- 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 for < 16 years

- An acceptable source of stem cells according to current University of Minnesota BMT
program guidelines:

- UCB graft will be composed of two partially HLA matched units. Each unit must be
matched at 4-6 HLA loci to the recipient and to each other. If two matched units
are not available, then a single HLA 4-6 matched unit may be used if of adequate
cell dose - total graft dose must be >3 x 107 MNC/kg

- HLA-matched related donor (6/6 or 5/6 antigen match)

- HLA-matched unrelated adult donor (if previously identified)

- 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