Calcineurin Inhibitor-Free GVHD Prevention Regimen After Related Haplo PBSCT
Condition: Non-Hodgkin's Lymphoma; Acute Leukemia in Remission; Chronic Myeloid Leukemia; Primary Myelofibrosis; Chronic Myelomonocytic Leukemia; Myelodysplastic Syndromes; Hodgkin Lymphoma; Multiple Myeloma
MeSH terms: Lymphoma; Leukemia; Leukemia, Myeloid; Multiple Myeloma; Lymphoma, Non-Hodgkin; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myelomonocytic, Chronic; Leukemia, Myelomonocytic, Juvenile; Myelodysplastic Syndromes; Primary Myelofibrosis
Intervention: Fludarabine; Busulfan; Cyclophosphamide; Total body irradiation (TBI); Peripheral Blood Hematopoietic Cell Transplantation (HCT); Sirolimus (SIR); Mycophenolate mofetil (MMF); Granulocyte-colony stimulating factor (G-CSF)
Intervention description: Myeloablative conditioning: 40 mg/m^2 daily for 4 days. Dose will be adjusted for estimated creatinine clearance. Reduced intensity conditioning: 30 mg/m^2 daily on days -6, -5, -4, -3 and -2. Dose will be adjusted for estimated creatinine clearance.; Myeloablative conditioning: IV dosing targeted for a daily total area under curve (AUC) 5300 mmol*min/L for 4 days. Busulfan AUC will be pharmacokinetically targeted. An AUC 3500 mmol*min/l may be considered in patients over 60 years of age or with multiple comorbidities. Chemotherapy may start on day -6 or day -5 depending on the day of admission (-6 for Wednesday admission, -5 for Sunday admission).; Reduced intensity conditioning: 14.5 mg/kg/day on days -6, -5. GVHD prophylaxis: 50 mg/kg ideal body weight (IBW) daily dose will be given on days +3 and +4 post-transplant as an IV infusion over 1-2 hours.; Reduced intensity conditioning: 200 centigray (cGy) on day -1.; On day 0, patients will receive a peripheral blood hematopoietic cell graft.; GVHD prophylaxis: SIR will be administered as a 9 mg oral loading dose on day +5, followed by maintenance. SIR levels will be monitored and maintenance dosing adjusted as needed for a target trough level 8 to 14 ng/ml, per Moffitt BMT program standard practice. In the absence of acute GVHD, sirolimus taper will start on day +90 (+/- 10 days) and it is suggested to finish by day +180.; GVHD prophylaxis: MMF will start on day +5 at a dose of 15 mg/kg every 8 hours IV with the maximum daily dose not to exceed 3 gm. MMF will be changed to orally (PO) and discontinued on day +35 (without taper) in the absence of acute GVHD.; Growth factor support: G-CSF will be given beginning on day 5 at a dose of 5 mcg/kg/day (rounding to the nearest vial dose), until absolute granulocyte count (ANC) is > 1,000/mm^3 for three consecutive days. G-CSF may be given IV or subcutaneously.
Intervention MeSH terms: Mycophenolic Acid; Sirolimus; Cyclophosphamide; Busulfan; Fludarabine; Lenograstim
Phase: Phase 1
Study type: Interventional
Primary purpose: Prevention
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 32.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Acute leukemia in CR; Chronic myeloid leukemia; Non-Hodgkin lymphoma in high risk; Graft vs. Host Disease; GVHD; Hematopoietic cell transplant (HCT)

Summary:

      The purpose of this study is to find out if a combination of drugs (these are called:
      cyclophosphamide, sirolimus, and mycophenolate mofetil) will protect participants better
      against graft vs. host disease (GVHD) after receiving a hematopoietic cell transplant from a
      related partially matched (haploidentical) donor. As part of the treatment for their blood
      cancer, participants need a hematopoietic cell transplantation (HCT) to improve their chances
      of cure. In any HCT, after the stem cell infusion is given, a combination of drugs is needed
      to prevent GVHD and facilitate acceptance of the graft.
    

Eligibility criteria:

        Inclusion Criteria:

        Patient Participants:

          -  Age: Must be older than 18 years, no upper age limit.

          -  Karnofsky performance status: Full intensity conditioning, 80-100%; reduced intensity
             conditioning, 60-100%.

          -  Vital organ function: a) Cardiac: Left ventricular ejection fraction must be > 45%
             assessed by multigated acquisition (MUGA) scan or echocardiogram. No myocardial
             infarction within 6 months of transplant evaluation. b) Pulmonary: forced expiratory
             volume at one second (FEV1), forced vital capacity (FVC), and adjusted diffusing
             capacity of the lungs for carbon monoxide (DLCO) must be ≥ 50% of predicted values. c)
             Liver: Transaminases (AST, ALT) less than 2 times upper limit of normal values. d)
             Kidney: Estimated creatinine clearance ≥ 50 cc/min.

          -  Signed informed consent.

          -  Included disease conditions and remission status: a) Acute leukemia in First Complete
             Remission (CR1) or second/subsequent CR. b) Chronic myeloid leukemia, primary
             myelofibrosis, chronic myelomonocytic leukemia. c) Int-2 or high risk myelodysplastic
             syndrome (MDS). d) Hodgkin lymphoma beyond CR1 with chemosensitive disease, Stable
             Disease (SD) may be included if no mass >3 cm. e) Non-Hodgkin lymphoma in high risk
             CR1 or subsequent CR (by clinical, cytogenetic or molecular criteria), primary
             induction failure (PIF) or relapsed with chemosensitive disease. SD may be included if
             no mass >3 cm. f) Multiple myeloma in CR/Very Good Partial Response (VGPR).

        Donor Participants:

          -  Per Moffitt Cancer Center (MCC) Blood and Marrow Transplant (BMT) program practices,
             an allele level matched (8/8 HLA A, B, C and DR) sibling or unrelated donor is
             preferred. If a matched donor is not found, mismatched unrelated or haploidentical
             donors may be considered.

          -  If a haploidentical donor is considered, parents, children, full siblings and in
             selected cases, extended family, will have high resolution typing at the MCC HLA
             laboratory. A familiar haploidentical donor is chosen among those who share at least
             one HLA-A, B, C, DRB1 and DQB1 haplotype with the patient.

          -  Patient will be screened for antibodies targeting mismatched HLA antigens in potential
             haploidentical donors (donor specific antibodies, DSA). Antibody screen and
             confirmatory testing using Luminex single antigen-bead test will be done.

          -  Among several potential donors, will choose in order of priority: a) Matched
             cytomegalovirus (CMV) immunoglobulin G (IgG) serologic status between donor and
             recipient. b) ABO blood group system-matched donor preferred, then minor ABO mismatch,
             then major ABO mismatch. c) Younger donor preferred: child, then sibling, and then
             parent. d) For male recipient, male donor will be preferred. Avoid mother as a donor
             unless no other choices.

        Exclusion Criteria:

        Patient Participants:

          -  Uncontrolled active bacterial, viral, fungal infection.

          -  Prior allogeneic HCT.

          -  Unwilling to comply with study requirements.

          -  Active, progressive or advanced disease based on diagnosis.