This study will investigate the safety and effectiveness of a modified donor stem cell
transplantation procedure for treating advanced mycosis fungoides (MF), a lymphoma primarily
affecting the skin, and Sezary syndrome (SS), a leukemic form of the disease. Donated stem
cells (cells produced by the bone marrow that mature into the different blood components
white cells, red cells and platelets) can cure patients with certain leukemias and lymphomas
and multiple myeloma. These cells generate a completely new, functioning bone marrow. In
addition, immune cells from the donor grow and generate a new immune system to help fight
infections. The new immune cells also attack any residual tumor cells left in the body after
intensive chemotherapy. However, stem cell transplantation carries a significant risk of
death, because it requires completely suppressing the immune system with high-dose
chemotherapy and radiation. In addition, lymphocytes from the donor may cause what is called
graft vs. host disease (GvHD), in which these cells see the patient s cells as foreign and
mount an immune response to destroy them. To try to reduce these risks, patients in this
study will be given low-dose chemotherapy and no radiation, a regimen that is easier for the
body to tolerate and involves a shorter period of complete immune suppression. In addition, a
monoclonal antibody called Campath-1H will be given to target lymphocytes, including those
that have become cancerous.
Patients with advanced MF or SS who are between 18 and 70 years of age and have a matched
family donor 18 years of age or older may be eligible for this study. Candidates will have a
medical history, physical examination and blood tests, lung and heart function tests, X-rays
of the chest, eye examination, and bone marrow sampling (withdrawal through a needle of about
a tablespoon of marrow from the hip bone), and small skin biopsy (surgical removal of a piece
of tissue for microscopic examination) or needle biopsy of the tumor.
Stem cells will be collected from both the patient and donor. To do this, the hormone G-CSF
will be injected under the skin for several days to push stem cells out of the bone marrow
into the bloodstream. Then, the stem cells will be collected by apheresis. In this procedure
the blood is drawn through a needle placed in one arm and pumped into a machine where the
required cells are separated out and removed. The rest of the blood is returned through a
needle in the other arm.
Before the transplant, a central venous line (large plastic tube) is placed into a major
vein. This tube can stay in the body and be used the entire treatment period to deliver the
donated stem cells, give medications, transfuse blood, if needed, and withdraw blood samples.
Several days before the transplant procedure, patients will start a conditioning regimen of
low-dose chemotherapy with Campath 1H, fludarabine, and, if necessary, cyclophosphamide. When
the conditioning therapy is completed, the stem cells will be infused over a period of up to
4 hours. To help prevent rejection of donor cells and GvHD, cyclosporine and mycophenolate
mofetil will be given by mouth or by vein for about 3 months starting 4 days before the
The anticipated hospital stay is 3 to 4 days, when the first 3 doses of Campath will be
monitored for drug side effects. The rest of the procedures, including the transplant, can be
done on an outpatient basis. Follow-up visits for the first 3 months after the transplant
will be scheduled once or twice a week for a physical examination, blood tests and symptoms
check. Then, visits will be scheduled at 6, 12, 18, 24, 30, 36, and 48 months
post-transplant. Visits for the first 3 years will include blood tests, skin biopsies, and
bone marrow biopsies.
Primary cutaneous T-cell lymphomas (CTCL) are a group of lymphoproliferative disorders
characterized by localization of neoplastic T cells to the skin at presentation. Mycosis
fungoides (MF) and its leukemic variant Sezary syndrome (SS) are the most prevalent forms of
CTCL. While early stage MF is restricted to patches and plaques involving the skin, most
patients eventually develop cutaneous tumors, generalized erythroderma, or dissemination to
peripheral blood, lymph nodes or visceral organs. Currently existing therapy of tumor-stage
and disseminated CTCL is palliative, with most patients dying within 1-5 years. The presence
of CD8+ cells in close proximity to dermal neoplastic infiltrates in early stages of the
disease, and the clinical response seen with some immunomodulatory agents suggests that CTCL
may be potential targets for immunotherapy-based interventions.
Allogeneic stem cell transplantation is a curative treatment modality successfully employed
in a number of hematologic malignancies. The curative effect of this approach is in part
mediated by donor-derived T lymphocytes with reactivity for patient leukemic cells. The power
of this graft versus leukemia effect (GVL) is best illustrated in patients with relapsed
Chronic Myeloid Luekema (CML) after an allogeneic bone marrow transplant, in whom a single
donor lymphocyte infusion (DLI) can induce remission. We hypothesize that neoplastic T cells
in MF/SS may similarly be susceptible to a graft vs. tumor (GVT) effect. Unfortunately,
advanced patient age and a 25% to 35% risk of transplant related mortality (TRM) preclude the
use of conventional 'dose- intensive' allogeneic peripheral blood stem cell transplantation
(PBSCT) in patients with advanced CTCL who might otherwise benefit from this approach. The
risk of TRM related to conditioning can be circumvented at least partially by using a
reduced-intensity conditioning regimen to prepare the patient for transplantation.
In this study, we will treat male and non-pregnant female subjects between the ages of 18 and
70 years (both inclusive) suffering from advanced MF/SS with an allogeneic peripheral blood
stem cell (PBSC) transplant from an HLA-matched family donor or an HLA matched (10/10 allele
level match) unrelated donor. A low intensity, nonmyeloablative conditioning regimen
employing the anti-CD52 monoclonal antibody Campath-1H (alemtuzumab) and fludarabine will be
used to induce host immunosuppression to facilitate donor hematopoietic and lymphoid
engraftment. We anticipate minimal host myelosuppression and consequently reduced early
transplant toxicity with this conditioning regimen. Immune and hematopoietic reconstitution
will be achieved by infusion of unmanipulated donor-derived granulocyte colony stimulation
factor (G-CSF) mobilized peripheral blood stem cells. Infusion of donor lymphocytes in
incremental doses will be used to promote engraftment or diease regression when indicated.
Cyclosporine A (CSA) will be used as prophylaxis against graft vs host disease (GVHD), with
dose adjustments made as necessary to favor complete donor chimerism and disease regression.
A total of up to 25 subjects (transplant recipients) will be treated on this protocol. The
primary end point of this study is efficacy (proportion of subjects achieving a complete
response). Other end points include assessment of donor-host chimerism in various
hematopoietic and lymphoid cells, overall response, incidence of acute and chronic GVHD,
graft failure, assessment of lymphoid subset reconstitution, transplant related morbidity and
mortality and disease-free and overall survival and the outcomes of transplantation by the
donor type (related vs. unrelated).
- INCLUSION CRITERIA-RECIPIENT:
Ages 18-70 years (both inclusive)
Stages IIb to IVb patients with MF (biopsy diagnostic or consistent with MF) who have
progressed despite at least one treatment regimen and all patients with SS
Anticipated median survival less than 5 years or debilitation as a result of their disease.
Recovery from acute toxicity of prior treatment for MF/SS (to less than or equal to grade 1
[CTCAE v3.0]) or stabilization of toxicity occurring from prior therapy for MF/SS.
ECOG performance status of 1 or less.
No major organ dysfunction precluding transplantation.
DLCO greater than or equal to 60 percent predicted
Left ventricular ejection fraction greater than or equal to 40 percent.
Less than or equal to 25 percent of liver involved with metastatic tumor by CT scan.
6/6 HLA matched family donor or 10/10 matched unrelated donor at the allelic level
Ability to comprehend the investigational nature of the study and provide informed consent.
INCLUSION CRITERIA-RELATED and UNRELATED DONOR:<TAB>
6/6 HLA- matched family donor or 10/10 HLA-matched unrelated donor
Age greater than or equal to 18 years
Ability to comprehend the investigational nature of the study and provide informed consent.
For unrelated donor, the NMDP unrelated donor inclusion criteria will be used as
outlined in document (http://bethematch.org/WorkArea/DownloadAsset.aspx?id=1960).
Donor eligibility will be completed per NMDP standards and in accordance with most recent
and stringent FDA guidelines.
EXCLUSION CRITERIA (ANY OF THE FOLLOWING)-RECIPIENT
Patient pregnant or lactating
Age greater than 70 or less than 18 years
ECOG performance status of 2 or more.
Psychiatric disorder or mental deficiency of the recipient or donor sufficiently severe as
to make compliance with the BMT treatment unlikely and making informed consent impossible.
Major anticipated illness or organ failure incompatible with survival from BMT and where
survival is considered insufficient to assess transplant outcome (i.e. less than 3 months).
DLCO less than 60 percent predicted
Left ventricular ejection fraction less than 40 percent
Serum creatinine greater than 2.0 mg/dl
Serum bilirubin greater than 4 mg/dl, transaminases greater than 5 times the upper limit of
History of other malignancies in the last five years with the exception of basal cell or
squamous cell carcinoma of the skin
Evidence for CNS metastatic disease
Disease involving greater than 25 percent of the liver radiographically.
EXCLUSION CRITERIA (any of the following)-RELATED AND UNRELATED DONOR:
Donor pregnant or lactating
Age less than 18 years
HIV positive (donors who are positive for hepatitis B (HBV), hepatitis C (HCV) or human
T-cell lymphotropic virus (HTLV-1) will be used at the discretion of the investigator
following counseling and approval from the recipient).
Sickling hemoglobinopathy including HbSS or HbsC (for unrelated donors, testing for
hemoglobinopathies will only be done when clinically indicated).
History of malignancy within 5 years except basal cell or squamous carcinoma of the skin.
Donor unfit to receive G-CSF and undergo apheresis (Uncontrolled hypertension, history of
Psychiatric disorder or mental deficiency of the donor sufficiently severe as to make
compliance with the BMT treatment unlikely and making informed consent impossible.