Mismatched Transplantation Using High-dose Post-transplant Cyclophosphamide
Condition: Blood Stem Cell Transplant Failure; Leukemia; Hematologic Malignancies
MeSH terms: Leukemia; Neoplasms; Hematologic Neoplasms
Intervention: Cyclophosphamide; Fludarabine; Melphalan; Mesna; Rituximab; Stem Cell Transplantation; Thiotepa; Tacrolimus; Mycofenolate mofetil; G-CSF
Intervention description: 50 mg/kg/day intravenous (IV) over 3 hours on Days 3 and 4.; 40 mg/m^2 IV over 1 hour on Days -6, -5, -4, and -3.; 140 mg/m^2 IV (or 100 mg/m^2 with reduced intensity Regimen 2) over 30 minutes on Day -8.; 10 mg/kg IV every 4 hours for a total of 10 doses starting just prior to first dose of Cyclophosphamide on Days 3 and 4.; CD20+ lymphoid malignancies: 375 mg/m2 on Day -13 followed by 1000 mg/m2 on Day -6, +1, and +8.; Infusion of donor's stem cells by vein on Day 0, may last anywhere from 15 minutes to several hours.; 5 mg/kg Regimen 1 (or 5 mg/kg with reduced intensity Regimen 2) IV over 4 hours on Day -7.; 0.015 mg/kg by vein or orally daily starting on Day +5 for 3 months; 15 mg/kg/dose orally three times a day starting on Day +5 to Day +100 or otherwise indicated; 5 mcg/kg/day subcutaneously starting Day 7 once a day daily until neutrophil recovery > 1000/mcl.
Intervention MeSH terms: Mycophenolic Acid; Cyclophosphamide; Melphalan; Thiotepa; Rituximab; Fludarabine; Fludarabine phosphate; Tacrolimus
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 176.0
Sex: All
Maximum age: 75 Years
Healthy volunteers: No
Keywords: Hematologic Neoplasms; Blood Disorders; Blood Cancer; Transplantation, Blood And Marrow; Acute myelogenous leukemia; Myelodysplastic syndrome; Acute lymphocytic leukemia; Aplastic anemia; Chronic myelogenous leukemia; Chronic lymphocytic leukemia; Myeloproliferative disease; Hodgkin's disease; Non-Hodgkin's lymphoma; Multiple myeloma; Cyclophosphamide; Fludarabine; Melphalan; Mesna; Rituximab; Tacrolimus; Prograf; Mycofenolate mofetil; MMF; CellCept; G-CSF; Filgrastim; Neupogen

Summary:

      The goal of this clinical research study is to learn about the safety of giving a stem cell
      transplant from a tissue-mismatched donor, followed by cyclophosphamide, to patients with
      certain types of blood disorders or blood cancers. Melphalan, thiotepa, and fludarabine will
      also be given before the transplant.

      Researchers will study the health status of these patients at 3 months after the transplant.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Patients < 55 years (Myeloablative regimen #1) or > 55 and </= 75 years or significant
             comorbidities (Reduced intensity regimen #2) old lacking a matched related volunteer
             donor identified in time for transplant for which a related haploidentical donor (</=
             7/8 allele match at the A, B, C, DR loci), a 7/8 allele matched related or unrelated
             donor is identified, or a matched unrelated donor (MUD). The patients must be
             diagnosed with a high-risk disease defined as following:

          2. Acute lymphocytic leukemia (ALL) in CR1 with high-risk features including adverse
             cytogenetics such as t(9;22), t(1;19), t(4;11), or MLL gene rearrangements; ALL in
             second or greater remission or ALL with relapsed disease, peripheral blood blasts <
             1000/microliter, ALL patients must show response to most recent received chemotherapy;

          3. Acute myeloid leukemia (AML) in CR1 with intermediate-risk disease or high-risk
             features defined as: Greater than 1 cycle of induction therapy required to achieve
             remission; Preceding myelodysplastic syndrome (MDS) or myeloproliferative disease;
             Presence of FLT3 mutations or internal tandem duplications; FAB M6 or M7
             classification; Adverse cytogenetics, -5, del 5q, -7, del7q, abnormalities involving
             3q, 9q, 11q, 20q, 21q, 17, +8 [> 3 abnormalities], peripheral blood blasts
             <1000/microliter, AML patients must show response to most recent received
             chemotherapy;

          4. AML in second or greater remission, primary induction failure and patients with
             relapsed disease, peripheral blood blasts <1000/microliter; patients > 55 years and
             </= 75 years need to be in morphologic remission at transplant (< 5% blasts).

          5. Myelodysplastic syndrome (MDS) with International Prognostic Scoring System (IPSS)
             intermediate-2 or higher; or therapy-related MDS

          6. Aplastic anemia with Absolute neutrophil count (ANC)<1000 and transfusion dependent
             after they failed immunosuppression therapy

          7. Chronic myeloid leukemia (CML) >/=1st chronic phase, after failed >/=2 lines of
             tyrosine kinase inhibitors; in accelerated or blast phase with > 30% bone marrow
             blasts;

          8. Prior allogeneic stem cell transplant more than 6 months from the first transplant, in
             remission.

          9. Chemotherapy-sensitive relapsed lymphoma (Complete or partial response), Hodgkin's or
             non-Hodgkin's lymphoma, no evidence of "bulky" disease (> 10 cm in diameter);

         10. Patients with chemo-sensitive CLL with persistent or recurrent disease after
             fludarabine-based regimens, no evidence of "bulky" disease (> 10 cm in diameter)

         11. Patients with poor prognosis multiple myeloma by cytogenetics (del13, del 17p, t(1;14)
             or t(14;16) or hypodiploidy, with advanced disease (stage>/=2) and /or relapsed after
             autologous stem cell transplant.

         12. Patients with myelofibrosis (Lille >0, transfusion dependency, progression to blast
             phase; however, in remission from AML) or chronic myelomonocytic leukemia (CMML).
             These patients will be treated with the reduced-intensity conditioning regimen #2 and
             will be subject to the same stopping rule as the group >/= 55 years or with
             comorbidities.

         13. Zubrod performance status 0-1 or Lansky PS greater or equal to 70%.

         14. Patients above >/=65 years old should have an age-adjusted co-morbidity index of </=
             3.

         15. Available donor able to undergo a bone marrow harvest. For matched unrelated donor
             transplants only: Peripheral blood stem cells may be collected if donor is unavailable
             for bone marrow harvest or if adequate bone marrow cannot be collected.

         16. Bilirubin </= 1.5 mg/dl (unless Gilbert's syndrome), ALT or AST </= 200 IU/ml.

         17. Serum creatinine clearance >/=50 ml/min (calculated with Cockcroft-Gault formula);
             Creatinine for children </=1.5 mg/dl or </=2 times upper limit of normal for age
             (whichever is less);

         18. Diffusing capacity for carbon monoxide (DLCO) >/= 45% predicted corrected for
             hemoglobin. For pediatric patients, if unable to perform pulmonary function, >/= 92%
             oxygen saturation with pulse oximetry.

         19. Left ventricular ejection fraction (LVEF) >/= 40%.

         20. Patient or patient's legal representative, parent(s) or guardian should provide
             written informed consent. Assent of a minor if participant's age is at least seven and
             less than eighteen years.

        Exclusion Criteria:

          1. HIV positive; active hepatitis B or C

          2. Patients with active infections. The PI is the final arbiter of the eligibility.

          3. Liver cirrhosis with greater than grade 1 stage 1 inflammation/fibrosis

          4. Uncontrolled central nervous system (CNS) involvement by tumor cells

          5. Patients with AML must have less than 30% bone marrow blasts and no peripheral blood
             blasts.

          6. History of another primary malignancy that has not been in remission for at least 3
             years. (The following are exempt from the 3-year limit: non-invasive nonmelanoma skin
             cancer, fully excised melanoma in situ [Stage 0], curatively treated localized
             prostate cancer, and cervical carcinoma in situ on biopsy or a squamous
             intraepithelial lesion on PAP smear.)

          7. Positive Beta human chorionic gonadotropin (HCG) test in a woman with child bearing
             potential defined as not post-menopausal for 12 months or no previous surgical
             sterilization.

          8. Inability to comply with medical therapy or follow-up.