Tacrolimus and Methotrexate With or Without Sirolimus in Preventing Graft-Versus-Host Disease in Young Patients Undergoing Donor Stem Cell Transplant for Acute Lymphoblastic Leukemia in Complete Remission
Condition: B-cell Childhood Acute Lymphoblastic Leukemia; Childhood Acute Lymphoblastic Leukemia in Remission; Graft Versus Host Disease; L1 Childhood Acute Lymphoblastic Leukemia; L2 Childhood Acute Lymphoblastic Leukemia; T-cell Childhood Acute Lymphoblastic Leukemia
MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Graft vs Host Disease
Intervention: thiotepa; cyclophosphamide; tacrolimus; methotrexate; sirolimus; total body irradiation
Intervention description: Given IV; Given IV; Given IV or orally; Given IV; Given orally; Part of the transplant preparatory regimen
Intervention MeSH terms: Sirolimus; Cyclophosphamide; Thiotepa; Methotrexate; Tacrolimus
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 146.0
Sex: All
Minimum age: 1 Year
Maximum age: 21 Years
Healthy volunteers: No

Summary:

      This randomized phase III trial is studying tacrolimus, methotrexate, and sirolimus to see
      how well they work compared to tacrolimus and methotrexate in preventing graft-versus-host
      disease in young patients who are undergoing donor stem cell transplant for intermediate-risk
      or high-risk acute lymphoblastic leukemia in second complete remission and high risk acute
      lymphoblastic leukemia in first remission. Giving chemotherapy, such as thiotepa and
      cyclophosphamide, and total-body irradiation before a donor stem cell transplant helps stop
      the growth of cancer cells. It also helps stop the patient's immune system from rejecting the
      donor's stem cells. The donated stem cells may replace the patient's immune cells and help
      destroy any remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted
      cells from a donor can also make an immune response against the body's normal cells. Giving
      tacrolimus, methotrexate, and sirolimus after the transplant may stop this from happening. It
      is not yet known whether tacrolimus and methotrexate are more effective with or without
      sirolimus in preventing graft-versus-host disease.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Histologically or cytologically confirmed acute lymphoblastic leukemia (ALL) in second
             complete remission (CR2) (M1 bone marrow, < 5% blasts by morphology) meeting the
             following criteria:

               -  Intermediate risk relapsed ALL in CR2 (may receive matched sibling
                  transplantation only) meeting 1 of the following criteria:

                    -  B-lineage ALL in CR2 after a late first bone marrow (BM) relapse (≥ 36
                       months after the initiation of primary chemotherapy) with or without
                       associated extramedullary disease

                    -  B-lineage ALL in CR2 after a very early isolated extramedullary relapse (<18
                       months from the initiation of primary chemotherapy)

               -  High risk relapsed ALL in CR2 (may receive other related donor, unrelated donor,
                  or matched sibling transplantation) meeting 1 of the following criteria:

                    -  In CR2 after an early first BM relapse (< 36 months from initiation of
                       primary chemotherapy)

                    -  T-lineage ALL in CR2 after a first BM relapse occurring at any time after
                       initiation of primary chemotherapy

                    -  Philadelphia chromosome-positive ALL in CR2 after a first BM relapse
                       occurring at any time after the initiation of primary chemotherapy

                    -  T-lineage ALL in CR2 after a very early isolated extramedullary relapse (<18
                       months from the initiation of primary chemotherapy)

               -  High risk de novo ALL in CR1 (may receive matched sibling, other
                  related/unrelated BM/PBSC or unrelated CB transplantation) meeting 1 of the
                  following criteria:

                    -  Patients with the presence of t(9;22) translocation (Ph+) detected by
                       cytogenetic or PCR analysis at initial diagnosis. For patients on AALL0622,
                       the criteria for transplant are 1) any patient with Ph+ ALL with an
                       available matched sibling donor or 2) any patient with Ph+ ALL that is
                       defined as high risk (MRD > 1% Day 29 or MRD > 0.01% end-Consolidation Block
                       2) with any available donor, related or unrelated. Patients enrolled on
                       AALL0622 are only eligible if they follow this algorithm.

                    -  Patients with the presence of extreme hypodiploidy (< 44 chromosomes or DNA
                       index of < 0.81) detected by cytogenetic/ploidy analysis at initial
                       diagnosis.

                    -  Patients with the presence of 11q23 (MLL) rearrangements detected by
                       cytogenetic or PCR analysis at initial diagnosis who are slow early
                       responders (M2/M3 at Day 14 or MRD > 0.1% at Day 29).

          -  Enrolled on an appropriate COG relapsed ALL clinical trial after completing the
             required study therapy (i.e., minimum 1 re-induction course (4-6 weeks) and 1 round of
             intensive consolidation chemotherapy (3-6 weeks). Patients with high risk ALL in CR1
             are eligible as soon as they have achieved a CR.

               -  Patients not on a COG relapsed ALL clinical trial are eligible provided they have
                  received ≥ 1 round of re-induction lasting 4-6 weeks and 1 round of intensive
                  consolidation chemotherapy lasting 3-6 weeks

          -  No B-cell ALL L3 morphology with evidence of myc translocation by molecular or
             cytogenetic technique

          -  No Down syndrome

          -  No evidence of active CNS or other extramedullary disease (i.e., no CNS2)

          -  Karnofsky performance status (PS) 60-100% (for patients > 16 years of age) OR Lansky
             PS 60-100% (for patients ≤ 16 years of age)

          -  Shortening fraction ≥ 27% by echocardiogram OR ejection fraction ≥ 50% by radionuclide
             angiogram

          -  ALT or AST < 5 times upper limit of normal

          -  Bilirubin < 2.5 mg/dL (unless an increase is attributable to Gilbert's syndrome)

          -  Creatinine clearance OR radioisotope glomerular filtration rate ≥ 70 mL/min

          -  FEV_1 ≥ 60% by pulmonary function tests (PFTs)

          -  FVC ≥ 60% by PFTs

          -  DLCO ≥ 60% by PFTs

          -  For children who are unable to cooperate for PFTs all of the following criteria must
             be met:

               -  No evidence of dyspnea at rest

               -  No exercise intolerance

               -  No requirement for supplemental oxygen therapy

          -  Not pregnant or nursing

          -  Negative pregnancy test

          -  Fertile patients must use effective contraception

          -  No HIV or uncontrolled fungal, bacterial, or viral infection

               -  Fungal infection acquired during induction therapy allowed provided there is a
                  significant response to antifungal therapy with minimal or no evidence of disease
                  by CT scan

          -  Other concurrent immunosuppressants allowed

          -  No prior allogeneic or autologous stem cell transplantation

          -  No prior or concurrent voriconazole unless prior voriconazole therapy is completed or
             a different agent is substituted for voriconazole prior to study entry

          -  No concurrent grapefruit juice during sirolimus administration