RATIONALE: Giving low doses of chemotherapy, such as melphalan and fludarabine, and a
monoclonal antibody, such as alemtuzumab, before a donor bone marrow or peripheral blood
stem cell transplant helps stop the growth of cancer cells. It also stops the patient's
immune system from rejecting the donor's stem cells. The donated stem cells may replace the
patient's immune system and help destroy any remaining cancer cells (graft-versus-tumor
effect). Sometimes the transplanted cells from a donor can also make an immune response
against the body's normal cells. Giving cyclosporine after the transplant may stop this from
PURPOSE: This phase II trial is studying how well fludarabine, melphalan, alemtuzumab, and
peripheral stem cell transplant work in treating patients with hematologic cancer.
- Evaluate the proportion of patients with lymphohematopoietic malignancies who achieve
durable hematopoietic reconstitution after receiving a nonmyeloablative regimen
comprising melphalan, fludarabine, and alemtuzumab followed by allogeneic hematopoietic
stem cell transplantation.
- Determine the incidence and characteristics of peritransplantation morbidity and
mortality (e.g., hepatic veno-occlusive disease or infections) in patients treated with
- Determine the incidence and severity of acute and chronic graft-versus-host disease in
these patients treated with this regimen.
- Determine the overall and disease-free survival at 1, 3, 6, 12, and 24 months after
transplantation in these patients.
- Determine the quality of bone marrow and peripheral blood chimerism at 1, 3, 6, 12, and
24 months after transplantation in these patients.
- Assess the kinetics of immune reconstitution in patients treated with this regimen.
OUTLINE: Patients are stratified according to donor type (HLA-matched related vs HLA-matched
unrelated, single HLA-allele disparate related, or unmatched) (HLA-mismatched related or
matched unrelated donor stratum closed to accrual as of 1/11/06).
Patients receive a nonmyeloablative regimen comprising alemtuzumab IV over 8 hours on days
-8 to -5, fludarabine IV over 30 minutes on days -8 to -4, and melphalan IV over 30 minutes
on days -3 and -2. Allogeneic peripheral blood stem cells or bone marrow is infused on day
Patients receive graft-versus host disease prophylaxis comprising cyclosporine IV every 12
hours beginning on day -1 and continuing orally as tolerated until day 100.
Patients are followed every 6 weeks for 6 months, every 3 months for 6 months, every 3-6
months for 1 year, and then annually thereafter or as clinically indicated.
PROJECTED ACCRUAL: A maximum of 50 patients (25 HLA-matched related and 25 HLA-mismatched
related or matched unrelated) will be accrued for this study within 2 years (HLA-mismatched
related or matched unrelated donor stratum closed to accrual as of 1/11/06).
- Disease criteria: This trial is primarily designed for: 1) patients with relapsed or
primary refractory non-Hodgkin's lymphoma, 2) chemosensitive relapsed or refractory
acute and chronic lymphocytic leukemias, 3) relapsed or primary refractory Hodgkin's
Disease, or advanced (Durie-Salmon stage II or III) multiple myeloma, advanced
Waldenstrom macroglobulinemia, who, by virtue of advanced age, intensity of prior
radiation and/or chemotherapy, history of prior toxicity associated with
chemo/radiotherapy or existing organ dysfunction, would be at undue risk of regimen
associated mortality if transplanted according to protocols involving myeloablative
- Patients with aggressive NHL histologies must have chemo/radiosensitive disease, or
have non-progressive disease, or have stable disease on therapy, and be ineligible
for an autologous HSC transplant because of disease in the marrow.
- Patients with chronic myeloid leukemia and high risk forms of acute myelogenous
leukemia or myelodysplastic syndromes are also eligible in the absence of an
alternative active higher priority allogeneic transplant protocol for which they are
- Age criteria: Patients may be up to 70 years of age. There is no lower age threshold.
Patients above the age of 70 may also participate, after evaluation and approval by
the BMT Service attendings.
- Absence of active or uncontrolled bacterial, viral, or fungal infection that would
contraindicate the use of myelosuppressive chemotherapy.
- Patients must have a healthy HLA-compatible donor, either a matched or single HLA
allele disparate related donor or a similarly compatible unrelated donor recruited
through the National Marrow Donor Program. Related donors must be willing to
participate as research subjects and be willing to receive G-CSF to mobilize PBPC and
undergo leukapheresis to donate PBSC. Unrelated donors identified by the NMDP may
elect to donate either PBSC after treatment with G-CSF, or bone marrow. These
unrelated donors will provide informed consent and their PBSC or bone marrow
donations will be obtained at a qualified donor center participating in the NMDP.
- Each patient must be willing to participate as a research subject and must sign an
informed consent form after discussion of the nature and risks of the study prior to
entering the protocol. Parents or legal guardians of patients who are minors will
sign the consent form for these patients after discussion of the nature and risks of
- Female patients who are pregnant or lactating.
- Active or uncontrolled viral (including HIV-1), bacterial or fungal infection.
- Severe renal insufficiency (creatinine >2.0 or creatinine clearance < 30mL/minute)
- Severe hepatic dysfunction, as defined by: total bilirubin greater than 2.5 mg/dL and
AST and ALT >3xnl, unless the liver is involved with disease.
- Severe cardiac insufficiency, defined as a resting left ventricular ejection of less
than 30% as measured by echocardiography or radionuclide cardiac angiography.
Patients on cardiac medications for congestive heart failure are eligible, as long as
their LVEF is greater than 30% on medication.
- Severe pulmonary insufficiency, as defined by an adjusted diffusing capacity of less
than 40% of predicted value.
- Karnofsky or Lansky score <40%