Mismatched Family Member Donor Transplantation for Children and Young Adults With High Risk Hematological Malignancies
Condition: Leukemia, Acute Lymphocytic (ALL); Leukemia, Myeloid, Acute(AML); Leukemia, Myeloid, Chronic(CML); Juvenile Myelomonocytic Leukemia (JMML); Hemoglobinuria, Paroxysmal Nocturnal (PNH); Hodgkin Lymphoma; Lymphoma, Non-Hodgkin (NHL); Myelodysplastic Syndrome (MDS)
MeSH terms: Lymphoma; Leukemia; Neoplasms; Preleukemia; Lymphoma, Non-Hodgkin; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Juvenile; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Hemoglobinuria; Myelodysplastic Syndromes; Hemoglobinuria, Paroxysmal
Intervention: CliniMACS; Stem cell transplantation; Fludarabine; Thioplex®; L-phenylalanine mustard; Mycophenolate mofetil; Rituxan™; Alemtuzumab; Cyclophosphamide; Anti-thymocyte globulin (Rabbit); G-CSF; Muromonab
Intervention description: Miltenyi Biotec CliniMACS stem cell selection device; An infusion of HLA mismatched family member donor stem cells processed through the use of the investigational Miltenyi Biotec CliniMACS device.; Transplant recipients will receive a conditioning regimen consisting of systemic chemotherapy and antibodies.; Transplant recipients will receive a conditioning regimen consisting of systemic chemotherapy and antibodies.; Transplant recipients will receive a conditioning regimen consisting of systemic chemotherapy and antibodies.; Transplant recipients will receive a conditioning regimen consisting of systemic chemotherapy and antibodies.; Transplant recipients will receive a conditioning regimen consisting of systemic chemotherapy and antibodies.; After January 2010, due to the unavailability of muromonab, transplant recipients received a conditioning regimen consisting of systemic chemotherapy and antibodies, including alemtuzumab.; Transplant recipients will receive a conditioning regimen consisting of systemic chemotherapy and antibodies.; Transplant recipients will receive a conditioning regimen consisting of systemic chemotherapy and antibodies.; Transplant recipients will receive a conditioning regimen consisting of systemic chemotherapy and antibodies.; Prior to January 2010, transplant participants received a conditioning regimen consisting of systemic chemotherapy and antibodies, including muromonab. Muromonab became unavailable from the manufacturer at that time and was replaced by alemtuzumab.
Intervention MeSH terms: Mycophenolic Acid; Cyclophosphamide; Melphalan; Mechlorethamine; Thiotepa; Rituximab; Fludarabine; Alemtuzumab; Thymoglobulin; Antilymphocyte Serum; Muromonab-CD3
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 73.0
Sex: All
Maximum age: 21 Years
Healthy volunteers: No
Keywords: Haploidentical stem cell transplant; Allogeneic stem cell transplant; Mismatched family member stem cell donor transplant; Bone marrow transplant; High risk hematologic malignancies; T cell depletion methodology; Miltenyi Biotec CliniMACS stem cell selection device; Campath-1H intravenous

Summary:

      Blood and marrow stem cell transplant has improved the outcome for patients with high-risk
      hematologic malignancies. However, most patients do not have an appropriate HLA (immune type)
      matched sibling donor available and/or are unable to identify an acceptable unrelated HLA
      matched donor through the registries in a timely manner. Another option is haploidentical
      transplant using a partially matched family member donor.

      Although haploidentical transplant has proven curative in many patients, this procedure has
      been hindered by significant complications, primarily regimen-related toxicity including GVHD
      and infection due to delayed immune reconstitution. These can, in part, be due to certain
      white blood cells in the graft called T cells. GVHD happens when the donor T cells recognize
      the body tissues of the patient (the host) are different and attack these cells. Although too
      many T cells increase the possibility of GVHD, too few may cause the recipient's immune
      system to reconstitute slowly or the graft to fail to grow, leaving the patient at high-risk
      for significant infection.

      For these reasons, a primary focus for researchers is to engineer the graft to provide a T
      cell dose that will reduce the risk for GVHD, yet provide a sufficient number of cells to
      facilitate immune reconstitution and graft integrity. Building on prior institutional trials,
      this study will provide patients with a haploidentical (HAPLO) graft engineered to specific T
      cell target values using the CliniMACS system. A reduced intensity, preparative regimen will
      be used in an effort to reduce regimen-related toxicity and mortality.

      The primary aim of the study is to help improve overall survival with haploidentical stem
      cell transplant in this high risk patient population by 1) limiting the complication of graft
      versus host disease (GVHD), 2) enhancing post-transplant immune reconstitution, and 3)
      reducing non-relapse mortality.
    

Eligibility criteria:

        Inclusion Criteria:(transplant recipient)

          -  Patients less than or equal to 21 years of age; may be greater than 21 years old if a
             current St. Jude patient or previously treated St. Jude patient within 3 years of
             completion of prior treatment.

          -  Must have one of the following diagnosis:

               -  ALL high risk in second remission. Examples include relapse on therapy, first
                  remission duration of less than or equal to 30 months, or relapse within 12
                  months of completing therapy.

               -  ALL in third or subsequent remission.

               -  ALL high risk in first remission. Examples include: induction failure, minimal
                  residual disease greater than or equal to 1% marrow blasts by morphology after
                  induction, persistent or recurrent cytogenetic or molecular evidence of disease
                  during therapy requiring additional therapy after induction to achieve remission.

               -  High-risk AML in first remission. Examples include monosomy 7, M6, M7, t(6;9),
                  FLT3-ITD, or patients who have greater than or equal to 25% blasts by morphology
                  after induction or who do not achieve CR after 2 courses of therapy (includes
                  myeloid sarcoma).

               -  Relapsed or persistent AML (less than or equal to 25% blasts in marrow by
                  morphology).

               -  AML in second or subsequent morphologic remission (includes myeloid sarcoma).

               -  CML in first chronic phase with detectable molecular or cytogenetic evidence of
                  disease despite medical therapy; or CML with a history of accelerated or blast
                  crisis, now in chronic phase; or unable to tolerate tyrosine kinase inhibitor
                  therapy.

               -  Juvenile myelomonocytic leukemia (JMML).

               -  Myelodysplastic syndrome (MDS).

               -  Therapy related (secondary) AML, ALL, or MDS.

               -  Hodgkin lymphoma after failure of prior autologous HSCT or unsuitable for
                  autologous HSCT.

               -  Non-Hodgkin lymphoma (NHL) in second complete remission (CR2) or subsequent.

          -  Has not received a prior allogeneic hematopoietic stem cell transplant.

          -  Does not have a suitable HLA-matched sibling donor available for stem cell donation.

          -  Does not have a suitable cord blood product or volunteer matched unrelated donor (MUD)
             available in the necessary time for stem cell donation.

          -  Has a suitable HLA partially matched family member available for stem cell donation.

          -  Cardiac shortening fraction greater than or equal to 25%.

          -  Creatinine clearance or glomerular filtration rate (GFR) greater than or equal to 40
             ml/min/1.73 m^2.

          -  Forced vital capacity (FVC) greater than or equal to 40% of predicted value or a pulse
             oximetry value of greater than or equal to 92% on room air.

          -  Direct bilirubin less than or equal to 3 mg/dl.

          -  Age-dependent performance score of greater than or equal to 50.

          -  Serum glutamic pyruvic transaminase (SGPT) less than 3 times the upper limit of normal
             for age.

          -  Karnofsky or Lansky (age-dependent) performance score of greater than or equal to 50.

          -  No known allergy to murine products or human anti-mouse antibody (HAMA) results within
             normal limits.

          -  Not pregnant (confirmed by negative serum or urine pregnancy test within 14 days prior
             to enrollment).

          -  Not breast feeding.

        Inclusion criteria (stem cell donor):

          -  Partially HLA matched family member.

          -  At least 18 years of age.

          -  Human immunodeficiency virus (HIV) negative.

          -  Not pregnant (confirmed by negative serum or urine pregnancy test within 7 days prior
             to enrollment).

          -  Not breast feeding.

        Inclusion criteria (transplant recipient - stem cell boost)

        Has experienced one of the following disorders post-transplant:

          -  graft failure

          -  graft rejection

          -  delayed hematopoietic and/or immune reconstitution.

        Exclusion: NA