Treatment Of Hematologic Malignancies With High-Dose Chemo-Radiotherapy Followed By Single-Unit Or Double-Unit Cord Blood Transplantation: A Phase II Study

Principal Investigator: Peter A. McSweeney, MD

Protocol Number: RMBMT-149

Major Objectives

Minor Objectives

1. Evaluate safety as measured by day 100 treatment related mortality.
2. Evaluate incidence of platelet engraftment
3. Evaluate incidences of acute and chronic GVHD
4. Evaluate efficacy as measured by survival at 1 and 2 years after transplant.
5. Evaluate chimerism from double cord transplants to determine source of long term engraftment

Patient Selection

Inclusion Criteria:

1. Be between the ages of 18 and 49 years inclusive.
2. Have histologically proven hematologic malignancy and must meet accepted indications for allogeneic stem cell transplantation:
   • Acute myeloid leukemia: high-risk in first CR, near first CR (< 20% marrow blasts after induction therapy), or beyond first remission.
   • Acute lymphoblastic leukemia with high-risk features in first remission (Philadelphia chromosome positive or other similar high-risk features), near first CR (< 20% marrow blasts after induction therapy), or beyond first remission.
   • Chronic myeloid leukemia: in CP have failed Gleevec or are intolerant and have signs or failing other treatments, or have history of accelerated or blast phases. Storage of autologous peripheral blood stem cells is recommended for this group for patients, particularly if in chronic phase.
   • Non-Hodgkin’s lymphoma; Aggressive histology with relapsed or primary refractory disease and not eligible for autologous transplantation. Patients with low-grade histology must have either failed 2 or more lines of systemic chemotherapy including one rituximab-based regimen. Radioimmunotherapy will be considered the equivalent of one line of chemotherapy. Excluded if prior radiotherapy to chest or prior autologous transplantation.
   • Myelodysplastic syndromes with IPSS score of 1.5 or greater.
   • Other hematological malignancies if approved by the pipeline meeting on a case by case basis. Must also be approved by principal investigator.
3. Have no HLA-matched or 1-antigen mismatched related donors and no HLA-matched unrelated stem cell donors, or delays involved in performing a search are likely to be detrimental to the patient.
4. Have an ECOG performance status of 0 or 1 at the time of transplant.
5. Have major end organs (heart, lungs, liver, and kidneys) assessed and deemed adequate to withstand the effects of high-dose therapy planned for this protocol.
6. Have given voluntary informed consent.

Exclusion Criteria:

1. Have a co-morbid medical condition, a psychiatric condition, or organ dysfunction that makes them at high-risk for treatment failure, for failed medical compliance, or for regimen-related toxicity from high-dose therapy.
2. Patients with any of the following will be excluded:
   • Pulmonary: Hb-adjusted DLCO < 60%, FEV1 < 70% of predicted, or receive continuous supplemental oxygen.
   • Cardiac LVEF < 50% or on any treatment for congestive heart failure;
   • Renal: serum creatinine greater than 2.0 or calculated creatinine clearance < 50 cc/min;
   • Liver: ALT, AST, or serum bilirubin > 1.5 x ULN. Any patient with elevated transaminases should have careful evaluation for the cause and liver biopsy may be required by the principle investigator. An elevated alkaline phosphatase should be fractionated and if of liver origin should be evaluated as for transaminases.
   • Are female and are pregnant, lactating, or have a positive pregnancy test.
   • Have a history of previous malignancy except non-melanoma skin cancer and in-situ carcinoma of the cervix, unless the patient has been progression-free for >5 years
   • Are HIV positive.
   • Refractory malignancy: Acute leukemia with greater than 30% blasts in bone marrow unless with untreated first relapse of AML or untreated myelodysplastic syndrome evolved to AML.
   • Acute leukemia with greater than 1000 blasts/ul in peripheral blood.
   • Uncontrolled CNS leukemia or lymphoma.
   • Prior autologous or allogeneic transplantation using a myeloablative regimen.
   • Uncontrolled hypertension (SBP >140, DBP >90) or hypertension requiring > 2 drugs for good control (SBP < 130, DBP <90).
   • Invasive mold infection that is uncontrolled or has received less than one month of antifungal therapy.

Donor Selection

Inclusion Criteria:

1. Single cord. Donor must be a 4/6 or better match with the recipient
2. Double Cord Both cords must be a 4/6 to 6/6 match with the recipients and a 4/6 match with each other. The mismatches to the recipient and between the cords do not have to involve the same loci.

• Single cord transplants: For transplants using a single cord unit, the unit must have ≥ 2.0 x 10⁷ TNC/kg and ≥ 1.7 x 10⁵ CD34+ cells/kg recipient weight. If cell dose from a single cord unit is < 4.0 10⁷ TNC/kg a second cord unit will be used if a suitable one can be found.
• Double cord transplants. The combined cell doses of two cords must include ≥ 2.5 x 10⁷ TNC/kg and ≥ 2.0 x 10⁵ CD34+ cells/kg recipient weight. The bigger of the two units much contain a minimum of 1.5 x 10⁷ TNC/kg.
• Source of Cord UnitsCord Blood Units will be obtained from established cord bank banks, preferably in North America. Cord blood units greater than 10 years old will not be used.