Targeted Marrow Irradiation, Fludarabine Phosphate, and Busulfan Before Donor Progenitor Cell Transplant in Treating Patients With Hematologic Malignancies

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose of targeted marrow irradiation given in
combination with fludarabine (fludarabine phosphate) and busulfan as conditioning regimen for
allogeneic hematopoietic progenitor cell transplantation.

SECONDARY OBJECTIVES:

I. To describe the toxicity profile of the conditioning regimen of targeted marrow
irradiation (TMI), fludarabine and busulfan for allogeneic hematopoietic progenitor
transplantation.

II. To describe the use of two techniques of delivering TMI, volumetric modulated arc therapy
(VMAT) and TomoTherapy, on patient's computed tomography (CT) simulation images and describe
differences in organ avoidance and target coverage, planning time, and treatment delivery
time.

III. To determine the disease response status 100 days after allogeneic hematopoietic
progenitor cell transplantation with the conditioning regimen of TMI, fludarabine and
busulfan.

IV. To determine the rates of acute graft versus host disease after allogeneic hematopoietic
progenitor cell transplantation with the conditioning regimen of TMI, fludarabine and
busulfan.

OUTLINE: This is a dose-escalation study of TMI.

CONDITIONING: Patients undergo TMI twice daily (BID) on days -10 to -7. Patients also receive
fludarabine phosphate intravenously (IV) over 1 hour on days -6 to -2 and busulfan IV or
orally (PO) on days -5 and -4.

TRANSPLANT: Patients undergo allogeneic hematopoietic progenitor cell transplant on day 0.

GRAFT-VERSUS-HOST DISEASE (GVHD) PROPHYLAXIS: Patients receive anti-thymocyte globulin IV on
days -3 and -2, tacrolimus IV or PO beginning on day -1 for at least 6 months with taper
beginning at 4 months, and methotrexate IV on days 1, 3, 6, and 11.

After completion of study treatment, patients are followed up at 100 days, 6 months, and 12
months.

Inclusion Criteria:

- Patients ineligible to receive full myeloablative conditioning regimen for allogeneic
hematopoietic progenitor cell transplant due to age or comorbidities

- Patients must have histologically or cytologically diagnosis of hematologic
malignancies with an indication for allogeneic hematopoietic progenitor cell
transplantation, who are ineligible to receive a full ablative conditioning regimen as
part of their transplantation, including:

- Acute myeloid leukemia

- Acute lymphocytic leukemia

- Non Hodgkin lymphoma

- Hodgkin lymphoma

- Multiple myeloma

- Myelodysplastic syndrome

- Chronic lymphocytic leukemia

- Chronic myeloid leukemia:

- Myeloproliferative syndromes including myelofibrosis

- Complete remission is not necessary for enrollment in this protocol

- Patients must have an allogeneic hematopoietic progenitor cell donor (HPCT), either a
matched sibling, mismatched (1 allele) sibling, or a matched unrelated donor (MUD) or
a mismatched (1 allele) unrelated donor

- Previous hematopoietic progenitor cell transplantation is allowed; a minimum of 6
months should have elapsed from prior autologous hematopoietic progenitor cell
transplantation and a minimum of 6 months should have elapsed since prior
allogeneic hematopoietic progenitor cell transplantation; prior transplantation
with conditioning regimens using total body irradiation is not allowed

- Eastern Cooperative Oncology Group (ECOG) performance status 0-2

- Life expectancy of > 12 weeks, in the opinion of and as documented by the investigator

- Patients must have adequate hepatic, and renal function as defined below: there is no
exclusion for the presence of cytopenias

- Total bilirubin ≤ 1.5 times the institutional upper limit of normal

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])
≤ 2.5 X institutional upper limit of normal

- Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≤
2.5 X institutional upper limit of normal

- Creatinine clearance (calculated by the Cockroft-Gault formula) ≥ 60 ml/min

- Pulmonary Function Tests (FEV1, FVC, DLCO) 40%.

- Women of child-bearing potential and men must agree to use adequate contraception
(double barrier method of birth control or abstinence) from the time of study entry,
for the duration of study participation and for 3 months after completing treatment;
should a woman become pregnant or suspect that she is pregnant while she or her
partner is participating in this study, she should inform the treating physician
immediately

- Subjects must have the ability to understand and the willingness to sign a written
informed consent document

Exclusion Criteria:

- Prior non-hematologic treatment toxicities must be resolved to ≤ grade 1 according to
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE)
version 4.0, with the exception of the following grade 2 toxicities: alopecia; dry
skin; spleen disorders, hearing impairment; tinnitus; hypothyroidism; hyperthyroidism;
endocrine disorders; blurred vision; cataracts; constipation; gastroesophageal reflux;
fatigue; abnormal coagulation tests INR and/or aPTT; weight gain or weight loss;
anorexia; glucose intolerance; hypoalbuminemia; hypokalemia; muscle weakness;
dysgeusia; paresthesias; peripheral motor and/or sensory neuropathy; hot flashes;
hypertension.

- Patients must not have received other investigational agents within 14 days of
initiation of the conditioning regimen

- Patients with untreated brain metastases should be excluded from this clinical trial

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to fludarabine and or busulfan or other agents used in this study

- Prior allogeneic hematopoietic progenitor cell transplantation

- Prior autologous hematopoietic progenitor cell transplantation if the conditioning
regimen included total body irradiation

- Patients with uncontrolled intercurrent illness including, but not limited to ongoing
or active infection, symptomatic congestive heart failure, unstable angina pectoris,
cardiac arrhythmia, or psychiatric illness/social situations that would limit
compliance with study requirements; this exclusion criterion does not include the
underlying disease for which the patient is undergoing hematopoietic progenitor cell
transplantation

- Pregnant or breastfeeding women are excluded from this study; breastfeeding should be
discontinued

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible

- Patients with a history of therapy with radiation therapy are excluded

- Due to technical limitations of TMI, patients must be no taller than 1.9 m (6 feet 4
inches), and no wider from elbow to elbow in the supine position than 60 cm.