This study will investigate the safety and effectiveness of a new stem cell transplant
procedure for treating chronic myelogenous leukemia (CML).
Transplantation of donated stem cells (cells produced by the bone marrow that mature into
the different blood components-white cells, red cells and platelets) is a very effective
treatment for CML. However, despite its success in a large number of patients, there is
still a significant risk of death from the procedure. In addition, it results in sterility
and leaves patients at increased risk for other cancers and for eye cataracts. These
complications result from the intensive chemotherapy and radiation patients receive before
the transplant to rid the body of cancer cells. In this study, radiation will not be used
and chemotherapy drugs will be given in lower doses to try to reduce the dangers of the
Patients with CML will be tested for matching with a donor (family member) and will undergo
a medical history, physical examination and several tests (e.g., breathing tests, X-rays,
and others) to determine eligibility for the study. Participants will then undergo
apheresis to collect lymphocytes (white blood cells important in the immune system). In
apheresis, whole blood is drawn through a needle in the arm, similar to donating a unit of
blood. The required component-in this case, lymphocytes-are separated and removed, and the
rest of the blood is returned through a needle in the other arm.
Each day starting five days before the transplant, the donor will be given an injection of
G-CSF, a drug that releases stem cells from the bone marrow into the blood stream. The
cells will be collected after the fifth injection and again after a sixth injection the
following day. Meanwhile, patients will be given cyclophosphamide and fludarabine, and
perhaps anti-thymocyte globulin, to prevent rejection of the donated cells.
On the day of the transplant, patients will be given cyclosporin to prevent
graft-versus-host-disease, a disease in which the donor cells react against the patient's
cells. They may also be given lymphocytes after the transplant to boost the immune system
and destroy leukemia cells. After 30, 60 and 100 days, bone marrow cells and circulating
lymphocytes will be checked to see how many are of donor cell origin. If less than 100
percent are of donor origin, more lymphocytes will be transfused. Patients will have
physical examinations and blood tests at least weekly for 3 months and then periodically for
CML is a disease which progresses to blast crisis within five years of onset despite medical
intervention. Allogeneic transplantation has provided a definitive cure for a large number
of patients. The International Bone Marrow transplant registry reports a 67% three-year
disease free survival for CML patients receiving a matched sibling transplant. However
there remains a 17-20% treatment-related mortality and significant long-term complications.
Myeloablative regimens with total body irradiation (TBI) are associated with certain
sterility, along with a significant incidence of cataracts and second malignancies. Efforts
to ameliorate this toxicity have led to the development of regimens lacking total body
irradiation. Although the follow-up period for patients receiving these regimens has not
been long enough to answer the question of long-term toxicity, it appears that the response
rate and the disease free survival are comparable to regimens containing TBI. In addition,
transplantation experience with aplastic anemia where TBI is not part of the regimen
indicates that treatment related mortality along with the risk of long-term sequela are
Non-myeloablative allogeneic peripheral blood stem cell transplants are currently being
investigated in phase I/II trials assessing engraftment efficacy and toxicity at a number of
transplant centers. Preliminary data, including our own experience with 30 patients
undergoing this type of procedure, has shown a high rate of complete donor engraftment with
a low toxicity profile. Two recent studies investigating non-myeloablative
allo-transplantation in standard risk patients revealed an extremely low rate of
transplant-related complications and mortality.
In this protocol we investigate non-myeloablative allogeneic PBSC transplantation in
patients with CML. The patient group under study would include all patients with chronic
phase CML having an HLA-identical sibling. In this protocol, eligible patients would be
treated with an allogeneic peripheral blood stem cell transplant from an HLA identical or
single HLA antigen-mismatched family donor, using an intensive immunosuppressive regimen
without myeloablation ("mini-transplant") in an attempt to decrease the transplant related
toxicities while preserving the anti-malignancy and/or anti-host marrow effect of the graft.
The low intensity non-myeloablative conditioning regimen should provide adequate
immunosuppression to allow stem cell and lymphocyte engraftment. T-cell replete,
donor-derived, granulocyte colony stimulating factor (G-CSF)-mobilized peripheral blood stem
cells (PBSC) will be used to establish hematopoietic and lymphoid reconstitution. We will
add back lymphocytes in patients with less than 100% donor T-cell chimerism in an attempt to
prevent graft rejection and enhance a graft-versus-malignancy effect.
The primary endpoint of this study is transplant related mortality (1 year survival). Other
end points include engraftment, degree of donor-host chimerism, incidence of acute and
chronic graft versus host disease (GVHD), transplant related morbidity, as well as
disease-free and overall survival.
Patients in chronic phase CML.
Age 10 to 50.
Informed consent given.
Availability of HLA identical or single HLA-locus mismatched family donor.
Females must not be pregnant or lactating.
Must not have ECOG performance status of 3 or more. Must not have a psychiatric disorder
or mental deficiency severe as to make compliance with the BMT treatment unlikely, and
making informed consent impossible.
Must not have major anticipated illness or organ failure incompatible with survival from
Must not have diffusion capacity of carbon monoxide (DLCO) less than 40% predicted.
Must not have left ventricular ejection fraction: less than 30%.
Must not have serum creatinine greater than 50% above normal as defined by age.
Must not have serum bilirubin greater than 4 mg/dl.
Must not have transaminases greater 5 x upper limit of normal.
Must not have other malignant diseases liable to relapse or progress within 5 years.
HLA identical or single HLA-locus mismatched family donor, up to 80 years old.
Informed consent given.
Females must not be pregnant or lactating.
Donor must be fit to receive G-CSF and undergo apheresis. (No controlled hypertension, no
history of congestive heart failure or unstable angina, thrombocytopenia).
Must be HIV negative. Donors who are positive for hepatitis B (HBV), hepatitis C (HBC)
or human T-cell lymphotropic virus (HTLV)-I will be used at the discretion of the