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

OBJECTIVES:

Primary

- Compare the post-transplant 2-year event-free survival of pediatric patients with
intermediate-risk or high-risk acute lymphoblastic leukemia (ALL) in second complete
remission undergoing allogeneic hematopoietic stem cell transplantation treated with
graft-versus-host disease (GVHD) prophylaxis comprising tacrolimus and methotrexate
with or without sirolimus.

Secondary

- Compare rates of relapses, transplant-related mortality, and acute and chronic GVHD in
these patients.

- Evaluate the relative contribution of resistance by ALL blasts to cytolytic therapy
(e.g., chemotherapy/irradiation) as a cause of relapse post-transplantation by
correlating ALL in vivo blast resistance with in vivo sirolimus, inhibition levels of
the mTOR pathway in patients treated with sirolimus, and altered resistance pathways in
ALL blasts measured by microarray analysis.

- Evaluate the relative contribution of resistance by ALL blasts to the donor immune
response as a cause of relapse post-transplantation by correlating the development of
donor anti-ALL T-cell response, the development of acute and/or chronic GVHD, and the
detection of altered ALL blast immunogenicity after transplant with increased minimal
residual disease, persistent recipient chimerism, and relapse.

OUTLINE: This is a randomized, open-label, multicenter study. Patients are stratified
according to risk (intermediate CR2 vs high CR2 vs very high CR1), donor type (matched
sibling vs unrelated or mismatched vs mismatched related), and stem cell source (filgrastim
[G-CSF]-primed bone marrow vs unprimed bone marrow vs bone marrow vs peripheral blood vs
umbilical cord blood).

- Preparative regimen: Patients undergo total-body irradiation twice daily on days -8 to
-6 and receive thiotepa IV on days -5 and -4 and cyclophosphamide IV on days -3 and -2.

- Allogeneic hematopoietic stem cell transplantation: Patients undergo allogeneic
hematopoietic stem cell transplantation on day 0.

- Graft-versus-host disease (GVHD) prophylaxis: Patients are randomized to 1 of 2
treatment arms.

- Arm I (experimental): Patients receive tacrolimus IV continuously or orally (when
able) daily beginning on day -2 followed by a taper beginning on day 42 and
continuing until day 98 (for patients undergoing matched sibling donor
transplantation) OR tacrolimus IV continuously or orally daily beginning on day -2
followed by a taper beginning on day 100 and continuing until day 180 (for
patients undergoing related, unrelated, or cord blood donor transplantation) in
the absence of GVHD. Patients also receive methotrexate IV on days 1, 3, and 6
(for patients with matched sibling and umbilical cord blood donors) OR days 1, 3,
6, and 11 (for patients with unrelated bone marrow and peripheral blood stem cell
donors) and oral sirolimus daily beginning on day 0 followed by a taper beginning
on day 180 and continuing until day 207.

- Arm II (control): Patients receive tacrolimus and methotrexate as in arm I. After
completion of study treatment, patients are followed periodically for
approximately 10 years.

PROJECTED ACCRUAL: A total of 236 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

- Histologically or cytologically confirmed acute lymphoblastic leukemia (ALL)* in
second complete remission (CR2) (M1 bone marrow, < 5% blasts by morphology) meeting
the following criteria:

- Eligible for matched sibling transplantation AND intermediate-risk disease
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**

- Eligible for other related donor, unrelated donor, or matched sibling
transplantation AND high-risk disease 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**
NOTE: *ALL defined as bone marrow with > 25% L1 or L2 lymphoblasts (i.e.,
M3 marrow). Patients with > 25% L3 marrow lymphoblasts and/or evidence of
c-myc translocation are considered to have Burkitt's lymphoma or mature
B-cell leukemia and are not eligible.

NOTE: **Less than 18 months after initiation of primary chemotherapy

- Enrolled on an appropriate COG relapsed ALL clinical trial meeting 1 of the following
criteria:

- Must proceed directly to transplantation after completing the required study
therapy (i.e., 1 induction course and 2 consolidation courses)

- 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)

PATIENT CHARACTERISTICS:

- 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

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- 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

- Other concurrent immunosuppressants allowed