Pilot Study of Reduced-Intensity Umbilical Cord Blood Transplantation in Adult Patients Wtih Advanced Hematopoietic Malignancies

Inclusion Criteria:

• Age 55-70 years, or < 55 years if deemed ineligible for conventional high dosechemotherapy by the UCSF SCT Committee or by protocol eligibility requirements formyeloablative therapy. Reasons for ineligibility for myeloablative therapy include:

• Poor cardiac function (i.e. LVEF < 40%)

• Poor pulmonary function (i.e. DLCO < 50%)

• Hepatic dysfunction

• Prior myeloablative therapy

• Availability of donor cord blood (one to three units) matching at > or equal to 4 of 6HLA antigens (A, B, and DR). HLA class I antigens will be determined by serologicmethods, and Class II antigens will be determined by high-resolution DNA typing.Typing will be confirmed by the UCSF Immunogenetics Department. The target UCB TNCdose is > or equal to 3.5 x 10(7) TNC/kg recipient weight, however the absoluteminimum TNC requirement is > 2.5 x 10(7) TNC per kilogram) based on cell counts priorto cryopreservation. Cord blood units will be obtained from all availableinternational banks.

• HLA identical or 1 antigen mismatched related donors or potential HLA-matchedunrelated donors (MUD) must NOT be readily available

• Disease types include:

• Acute myeloid leukemia not expected to be curable with chemotherapy. This willinclude patients with high-risk cytogenetics (-7, -7q, -5, -5q, t(6, 9), t(9, 11), complex (> or equal to 3 abnormalities), Ph(+), evolution from priormyelodysplasia or AML secondary to prior chemotherapy, failure to achieveremission, second, or subsequent remission or refractory relapse. Marrow blastsmust be < or equal to 10%. This may be achieved using standard chemotherapytreatment.

• Myelodysplasia with high-risk features. This will include patients with IPSScategory INT2 or HI-risk MDS or CMML. Marrow blasts must be < or equal to 20%. Ifrequired, chemotherapy may be given to achieve target levels of blasts. Patientsare expected to have disease control or not rapidly progressive diseaseregardless of blast count (but must be < or equal to 20%).

• Acute lymphoblastic leukemia not expected to be cured with chemotherapy. Thiswill include patients with high-risk cytogenetics (Ph+, t(4,11), 11q23abnormalities, and monosomy 7), patients requiring more than one induction courseto achieve remission, as well as patients failing to enter remission or in secondor subsequent remission. Marrow blasts must be < or equal to 10%. If required,chemotherapy may be given to achieve target level of blasts.

• Chronic myelogenous leukemia- chronic phase failing imatinib mesylate therapy (either progressive disease or failure to achieve a major cytogenetic response at 1 year following initiation of therapy), accelerated phase failing to achieve acomplete cytogenetic remission at 1 year following initiation of therapy,accelerated phase failing to achieve any cytogenetic response at 6 months oftherapy, accelerated phase with progressive disease as demonstrated by worseningcytogenetic response in two consecutive analyses separated by 4 weeks or CML inblast crisis. Patients with blast phase of CML must have < 10% blasts in bonemarrow.

• Multiple myeloma stage I-III with relapse following autologous transplant, withdisease refractory to at least two prior conventional; myeloma therapies or withchromosome 13 abnormalities. Patients with chromosome 13 abnormalities areeligible either at diagnosis or after initial progression.

• Lymphomas including diffuse or follicular large cell lymphoma, mantle celllymphoma, peripheral T-cell lymphoma, T-NK cell lymphoma, or Hodgkin's diseasewhich has failed to respond to primary therapy, progressed, or recurred afterprior therapy. Patients who have relapsed following autologous transplant areeligible.

• Low-grade NHL and Chronic Lymphocytic Leukemia with relapse or refractory diseasefollowing, at least, two chemotherapy-based treatment regimens; or with relapsefollowing autologous transplantation.

• Patients must have an ECOG PS < or equal to 2.

• Laboratory requirements:

• Creatinine < 2.0mg/dL and creatinine clearance > 40/m/min (calculated or based on 24-hour urine collection)

• Bilirubin <2.0mg/dL, AST/alkphos <3x upper limit of normal

• Patients with hepatitis C and active hepatitis B (hepatitis B DNA detectable) areeligible only if a liver biopsy is performed and there is grade < or equal to 2fibrosis and/or inflammation. Patients with a history of HBV infection should betested for HBeAg, anti-HBe and HBV DNA (quantitative). Patients with active HBVviral replication should receive anti-viral therapy.

• Cardiac ejection fraction > 30%, DLCO > or equal to 40%.

• Negative pregnancy test (for females of reproductive age only).

• Signed informed consent

Exclusion Criteria:

• Active infection requiring ongoing antibiotic treatment

• HIV infection

• Poor performance status (ECOG > 2)

• Opinion of BMT Committee that autologous SCT or conventional therapy would be apreferable form of treatment

• Organ function is below requirements

• Pregnancy, or breast-feeding