Hematopoietic Cell Transplantation for Pediatric Patients With Hematologic Malignancies
Condition: Acute Leukaemia; Chronic Disease; Leukemia; Myelodysplasia; Lymphoma
MeSH terms: Leukemia; Neoplasms; Hematologic Neoplasms; Preleukemia; Myelodysplastic Syndromes; Chronic Disease
Intervention: Busulfan; Anti-Thymocyte Globulin; Fludarabine; Cyclosporine; Mycophenolate mofetil
Intervention description: This drug is a bifunctional alkylating agent. Busulfan is highly toxic to noncycling or slowly-cycling cells. Pharmacokinetic studies of the IV formulation in pediatrics have shown that using a dose of 0.8mg/kg IV q6 hours most patients will achieve AUC levels between 800 and 1300 uM/min, representing steady state levels between 600-900ug/ml. The manufacturer recommends higher doses, 1.1mg/kg for children less than 12kg. Because this is a reduced intensity study and infants on the study will be very heavily pretreated we will use the lower dose of 0.8mg/kg q6 hours for a total of 8 doses for all patients.; Thymoglobulin will be administered at a dose of 2.5 mg/kg recipient body weight intravenously on each of 4 successive mornings (Days -4, -3,-2,-1) for patients receiving unrelated grafts and at a dose of 2.5mg/kg as a single dose on d-1 for patients receiving related marrow grafts. ATG is infused over a minimum of 4 hours, but is generally better tolerated over 6-8 hours. Suggested premedications are acetaminophen (10 mg/kg/dose), diphenhydramine (1 mg/kg/dose), and methylprednisolone. The methylprednisolone should be given at a dose of
1mg/kg 30 minutes prior to the ATG, with another 1mg /kg four hours into the infusion (total 2mg/kg/d). Patients are observed continuously for possible allergic reactions throughout the infusion.; Administration and Dosage: Fludarabine will be administered at a dose of 30 mg/m2 in 100 ml of D5W intravenously over one hour on each of six consecutive days -10 through -5 for unrelated grafts or d-7 through d-2 for related grafts. Fludarabine is a fluorinated nucleotide analog of the antiviral agent vidarabine, 9-beta-D-arabinofuranosyladenine. Fludarabine phosphate is rapidly dephosphorylated to 2-fluoro-ara-A and then phosphorylated intracellularly by deoxycytidine kinase to the active triphosphate, 2-fluoro-ara-ATP. The half-life of 2-fluoro-ara-A is approximately 10 hours. The mean total plasma clearance is 8.9 L/hr/m2 and the mean volume of distribution is 98 L/m2. Approximately 23% is excreted unchanged. This metabolite appears to act by inhibiting DNA polymerase alpha, ribonucleotide reductase and DNA primase, thus inhibiting DNA synthesis.; Cyclosporine is a potent immunosuppressive agent that in animals prolongs survival of allogeneic transplants involving skin, kidney, liver, heart, pancreas, bone marrow, small intestine, and lung. The effectiveness of cyclosporine results from specific and reversible inhibition of immunocompetent lymphocytes in the G 0 - and G
1 -phase of the cell cycle. Administration and Dosage: Cyclosporin start on day -3 initially at a dose of 2.5mg/kg IV q12 hours or 3mg/kg/dose (neoral equivalent) PO q12 hours targeting suggested troughs of 250 to 350 ng/ml. Continuous infusion cyclosporin may be allowed per institutional preference. 3x daily dosing may be used for younger children to achieve therapeutic levels. PBMTC Protocol #ONC0313 19 Continuous infusion cyclosporin may be allowed per institutional preference.; MMF is a potent, selective, uncompetitive, and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), and therefore inhibits the de novo pathway of guanosine nucleotide synthesis without incorporation into DNA. Administration and Dosage: Initial dosage will be IV or PO with switch to PO when tolerated. Starting doses will be 15 mg/kg/day bid (total dose 30mg/kg/d, IV same as PO dose) beginning day 0 with the first dose given approximately 4-6 hours after the stem cell infusion. This dose will stop on day +30 for patients receiving matched sibling BM/PBSC and UCB grafts, but will continue until day +40 and then taper at approximately 11%/wk over 8 weeks until patients are off at day +96.
Intervention MeSH terms: Cyclosporine; Mycophenolic Acid; Fludarabine; Busulfan; Cyclosporins; Thymoglobulin; Antilymphocyte Serum
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 47.0
Sex: All
Maximum age: 21 Years
Healthy volunteers: No
Keywords: cancer; Hematologic Malignancies; Hematopoietic Cell Transplantation

Summary:

      This is a phase II trial of reduced intensity conditioning with Bu/Flu/ATG in pediatric
      patients with hematologic malignancies at high risk for transplant related mortality with
      standard transplantation. Patients qualify based on organ system dysfunction, active but
      stable infection, history of previous transplant or late stage disease. We plan to enroll 45
      patients through the Pediatric Blood and Marrow Transplant Consortium (PBMTC) and anticipate
      that the outcome of the trial will pave the way for phase II or III disease specific
      protocols addressing efficacy of the approach compared to standard transplant approaches in
      better risk patients.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Patients must be age 21 or younger and must have hematologic malignancies treatable
             with allogeneic hematopoietic transplantation (acute and chronic leukemias,
             myelodysplasia or lymphomas, see protocol for further details). Patients qualify for
             this approach in four ways: 1) presence of organ system dysfunction or severe systemic
             infections that significantly increase transplant related mortality with standard
             myeloablative transplant regimens, 2) history of previous myeloablative allogeneic or
             autologous transplantation, 3) currently in a third or higher CR receiving an
             unrelated stem cell transplant, or 4) a combination of toxicities that leads the
             investigator to feel that the child is at high risk (>50%) of TRM. Patients eligible
             for inclusion based on consideration number 4 above cannot be enrolled unless
             discussed with the study chair.

          2. Organ system dysfunction: at least one of the following organ system dysfunction
             criteria plus minimum organ function listed in exclusion criteria qualify a patient
             for treatment on this protocol

               1. Pulmonary: DLCO, FEV1 or TLC/FVC <60% predicted. Patients too young for PFTs with
                  suspected pulmonary toxicity should be assessed by a consulting pulmonologist. If
                  the pulmonologist judges the child to have moderate-severe pulmonary disease they
                  qualify for inclusion.

               2. Renal: creatinine clearance <60ml/m/1.73m2

               3. Hepatic: transaminases >4x normal or total bilirubin >2.0

               4. Cardiac: all patients with suspected cardiac toxicity should undergo a cardiac
                  echo. If the shortening fraction (SF) is <25% a measurement of ejection fraction
                  must be obtained. Patients qualify for reduced intensity therapy if the SF is
                  <25% and the EF <50%.

          3. Infections: Patients with responsive but unresolved invasive infections. These
             infections may be fungal, bacterial or other opportunistic infections. Viral
             infections do not meet this eligibility criteria.

          4. Other patient groups at high risk for transplant related mortality: Patients with a
             history of a prior allogeneic or autologous transplantation and patients who are in
             CR3 or greater and receiving an unrelated stem cell transplant are also eligible for
             this protocol. If the investigator feels that a patient has a combination of risk
             factors that could increase their risk of transplant related mortality to >50% with
             standard transplantation they may be eligible for inclusion, but such patients must be
             reviewed with the protocol chairman prior to enrollment.

        Exclusion Criteria:

          1. Patients must be in a CR (<5% blasts on BM morphology, no active CNS disease, see
             protocol) with the following exceptions:

               1. AML may proceed with M2 marrow status (<20% blasts).

               2. Lymphoma: residual disease must be responsive and non-bulky (<5cm largest
                  diameter).

               3. Myelodysplasia: Patients with RA, and RAEB are eligible, but RAEB-IT patients are
                  only eligible if treated to <5% blasts (RA) with chemotherapy.

               4. CML-BP must be treated to CR/CP2 to be eligible.

          2. Females who are pregnant

          3. Patients who are HIV positive or who have other progressive infections

          4. Organ dysfunction: patients are ineligible for the following levels of severe organ
             system dysfunction:

               1. Cardiac: Ejection fraction <30%

               2. Pulmonary: Receiving continuous supplementary oxygen or any of the following:
                  DLCO <30%, FVC/TLC < 30% or FEV1 <30%

               3. Hepatic: patients will be excluded for hepatic synthetic dysfunction evidenced by
                  any of the following: prolongation of the prothrombin time with an INR >2.0,
                  total serum bilirubin >3, or transaminases >10x normal.

               4. Renal: patients with a creatinine clearance <30ml/m/1.73m2 or who require
                  dialysis are not eligible

        Donor Eligibility Criteria:

          1. Related or unrelated donor who is a 6/6 HLA match at HLA-A, B, and DRB1 locus. 5/6
             matches are acceptable with mismatches at class I alleles (A and B), but DRB1
             mismatches are not allowed. Intermediate resolution typing of class I and high
             resolution typing of class II alleles is required. (HLA-C and HLA-DQ matching is
             encouraged, but not required with the ideal donor matching at 10/10 alleles.)

          2. Unrelated cord blood may be used if matched at HLA-A, B and DRB1 at either 4/6, 5/6,
             or 6/6 antigens. The minimum mononuclear cell dose required for eligibility is 3 x 107
             mononuclear cells/kg recipient body weight (based on frozen cell dose). It is strongly
             suggested that a back up unit of umbilical cord blood be reserved, though not
             requested, in case of rejection.

        Donors must pass required institutional and NMDP health and infectious disease screening.