Acute Myeloid Leukemia T Cell Depletion to Improve Transplants in Adults With Acute Myeloid Leukemia (BMT CTN 0303)

BACKGROUND:

Allogeneic hematopoietic cell transplantation is an accepted therapy for AML. Transplants of
unmodified HLA-matched related bone marrow or peripheral blood stem cells following
conditioning with total body irradiation (TBI) and cyclophosphamide or VP-16 or busulfan and
cyclophosphamide have led to sustained DFS rates of 45-60% for adults transplanted in first
complete remission (CR1) and 40-53% for patients transplanted in second complete remission
(CR2). In several single center and multicenter cooperative group prospective trials
comparing HLA-matched allogeneic transplants to chemotherapy in the treatment of AML in CR1,
DFS rates for the transplant arm were almost invariably superior; however, these advantages
were statistically significant in only a minority of the cooperative group studies conducted.
In each study, the risk of relapse was significantly lower for patients receiving allogeneic
transplants. However, this advantage was counterbalanced by transplant-related mortality,
principally reflecting infections complicating GVHD and its treatment.

DESIGN NARRATIVE:

Despite increased risks of infection, development of effective T cell depletion (TCD)
techniques for prevention of GVHD and tolerable modifications of regimens for pre-transplant
cytoreduction that secure consistent engraftment offer the potential for significant
decreases in transplant-related mortality. Furthermore, the use of TCD transplants in the
treatment of patients with AML is not associated with substantial increases in the incidence
of relapse. Several single center trials indicate highly encouraging long-term results,
particularly for patients with AML in CR1 or CR2. Although the number of cases in each single
center series is limited, the consistency of the results suggests that the use of an
effective technique for TCD together with an adequate cytoreductive regimen might yield
transplant results superior to those achieved with unmodified grafts.

Inclusion Criteria:

- Patients with AML with or without prior history of myelodysplastic syndrome based on
the World Health Organization criteria at the following stages:

- First morphologic complete remission (CR)

- Second morphologic CR

- If prior history of central nervous system (CNS) involvement, no evidence of active
CNS leukemia during the pre-transplant evaluation (no evidence of leukemic blasts in
cerebrospinal fluid)

- First or second CR was achieved after no more than two cycles of induction (or
re-induction for patients in second CR) chemotherapy

- No more than 6 months elapsed from documentation of CR to transplant for patients in
first CR, or 3 months for patients in second CR.

- A 6/6 HLA antigen (A, B, DRB1)-compatible sibling donor; the match may be determined
at serologic level for HLA-A and HLA-B loci; DRB1 must be matched at least at
low-resolution using DNA typing techniques; HLA-C will be typed at the serologic
level, but not included in the match algorithm

- Karnofsky performance status greater than 70%

- Life expectancy greater than 8 weeks

- Diffusing capacity of the lung for carbon monoxide (DLCO) of at least 40% (corrected
for hemoglobin) with no symptomatic pulmonary disease

- Left ventricular ejection fraction (LVEF) by Multi Gated Acquisition Scan (MUGA) or
echocardiogram greater than 40%

- Serum creatinine greater than 2 mg/dL, bilirubin greater than 2 mg/dL, and alanine
aminotransferase (ALT) and aspartate aminotransferase (AST) levels at least 3 times
the upper limit of normal at time of enrollment

- Willingness of both the patient and the donor to participate

Exclusion Criteria:

- M3-AML (acute promyelocytic leukemia) in first CR

- Acute leukemia following blast transformation of prior chronic myelogenous leukemia
(CML) or other myeloproliferative disease

- M4Eo-AML with inv 16 in first CR

- AML with t(8;21) in first CR

- Participation in other clinical trials that involve investigational drugs or devices
except with permission from the Medical Monitor

- Evidence of active Hepatitis B or C infection or evidence of cirrhosis

- HIV positive

- Uncontrolled diabetes mellitus

- If proven or probable invasive fungal infection, infection must be controlled;
patients may be on prophylactic anti-fungal agents, but are not permitted to be on
anti-fungal agents for therapeutic purposes (i.e., active treatment for disease)

- Uncontrolled viral or bacterial infection (currently taking medication without
clinical improvement)

- Documented allergy to iron dextran or murine proteins

- Pregnant or breastfeeding; women of childbearing age must avoid becoming pregnant
while in the study

- Prior autologous or allogeneic hematopoietic stem cell transplantation (HSCT)