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
Conditions
Brief 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.
Detailed description
PRIMARY OBJECTIVES: I. 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 or high risk ALL in first remission undergoing allogeneic hematopoietic stem cell transplantation treated with graft-versus-host disease (GVHD) prophylaxis comprising tacrolimus and methotrexate with or without sirolimus. SECONDARY OBJECTIVES: I. Compare rates of relapses, transplant-related mortality, and acute and chronic GVHD in these patients. II. 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. III. 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 specific combinations of risk (intermediate CR2 vs high CR2 vs high CR1), donor type (matched sibling vs unrelated or other 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 5 years.
Interventions
DRUGtacrolimus
Given IV or orally
DRUGmethotrexate
Given IV
DRUGsirolimus
Given orally
RADIATIONtotal body irradiation
Part of the transplant preparatory regimen
DRUGthiotepa
Given IV
DRUGcyclophosphamide
Given IV
Sponsors
National Cancer Institute (NCI)
Children's Oncology Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to 21 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Estimated Percentage of Participants With Event Free Survival | at 2 years | An event is defined as relapse or transplant-related mortality. Relapse is defined in section 3.3 study protocol. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Relapses | At 2 years | An event is defined as relapse. |
| Estimated Transplant Related Mortality Percentage | 100 days | Death in a patient who had not relapsed after transplant is defined as transplant-related mortality event. |
| Estimated Rate of Acute Graft VS Host Disease (GVHD) | At 200 days | Any grade acute graft vs host disease (defined in APPENDIX II study protocol). |
| Estimated Rate of Overall Chronic Graft VS Host Disease | At 2 years | Chronic graft vs host disease is defined in APPENDIX III of study protocol. |
| Relative Contribution of Resistance by Acute Lymphoblastic Leukemia (ALL) Blasts to Cytolytic Therapy (e.g., Chemotherapy/Irradiation) as a Cause of Relapse Post-transplantation | Up to 1 year | An event is defined as relapse or transplant-related mortality. |
| Relative Contribution of ALL Blasts to the Donor Immune Response as a Cause of Relapse Post Transplantation (Correlating Development of aGVHD With Relapse) | At 1 year | An event is defined as relapse; estimated probability of relapse. |
| Relative Contribution of ALL Blasts to the Donor Immune Response as a Cause of Relapse Pre-Transplantation (MRD) | At 2 months | An event is defined as relapse; relapse risk is reported. Not able to be performed given the low numbers of blast samples available. |
| Chimerism | Up to 12 months | Evaluate the relative contribution of resistance by ALL blasts to the donor immune response as a cause of relapse post transplantation. |
Countries
Australia, Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Tacro-MTX/Sirolimus GVHD Prophylaxis Regimen Preparative regimen of total body irradiation (TBI) 200 cGy BID days -8,-7, & -6, Thiotepa IV (dose 5 mg/kg/day on days -5 & -4) & cyclophosphamide IV (dose 60 mg/kg/day on days -3 & -2). Tacrolimus IV (dose 0.02 mg/kg/day) continuously or orally daily on day -2 with a taper starting on day 42 - day 98 (patients undergoing matched sibling donor transplantation) OR tacrolimus IV (dose 0.02 mg/kg/day) continuously or orally daily beginning on day -2 followed by a taper on day 100 through day 180 (patients undergoing other related, unrelated, or cord blood donor transplantation) in the absence of GVHD. Patients also receive methotrexate IV (5 mg/m2/dose) on days 1,3, & 6 (patients with matched sibling and umbilical cord blood donors) OR days 1,3 6, & 11 (patients with other related/unrelated bone marrow and peripheral blood stem cell donors) and oral sirolimus (dose 2.5mg/m2/day - 4 mg max starting dose) daily starting on day 0 followed by a taper starting on day 180 through day 207. | 76 |
| Tacro-MTX GVHD Prophylaxis Preparative regimen of total body irradiation (TBI) 200 cGy BID days -8,-7, & -6, Thiotepa IV (dose 5 mg/kg/day on days -5 & -4) & cyclophosphamide IV (dose 60 mg/kg/day on days -3 & -2). Tacrolimus IV (dose 0.02 mg/kg/day) continuously or orally (when able) daily on day -2 with a taper starting on day 42 - day 98 (patients undergoing matched sibling donor transplantation) OR tacrolimus IV (dose 0.02 mg/kg/day) continuously or orally daily beginning on day -2 followed by a taper on day 100 through day 180 (patients undergoing other related, unrelated, or cord blood donor transplantation) in the absence of GVHD. Patients also receive methotrexate IV (5 mg/m2/dose) on days 1,3, & 6 (patients with matched sibling and umbilical cord blood donors) OR days 1,3 6, & 11 (patients with other related/unrelated bone marrow and peripheral blood stem cell donors). | 70 |
| Total | 146 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 0 |
| Overall Study | consent withdrawal | 0 | 1 |
| Overall Study | ineligible | 2 | 0 |
| Overall Study | Other | 0 | 2 |
| Overall Study | Physician Decision | 6 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Tacro-MTX/Sirolimus GVHD Prophylaxis Regimen | Tacro-MTX GVHD Prophylaxis | Total |
|---|---|---|---|
| Age, Continuous | 9 Year | 10 Year | 9 Year |
| Ethnicity (NIH/OMB) Hispanic or Latino | 23 Participants | 16 Participants | 39 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 51 Participants | 53 Participants | 104 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 6 Participants | 11 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 10 Participants | 12 Participants | 22 Participants |
| Race (NIH/OMB) White | 59 Participants | 51 Participants | 110 Participants |
| Region of Enrollment Australia | 2 participants | 6 participants | 8 participants |
| Region of Enrollment Canada | 3 participants | 2 participants | 5 participants |
| Region of Enrollment United States | 71 participants | 62 participants | 133 participants |
| Sex: Female, Male Female | 30 Participants | 29 Participants | 59 Participants |
| Sex: Female, Male Male | 46 Participants | 41 Participants | 87 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 38 / 72 | 30 / 70 |
| serious Total, serious adverse events | 9 / 72 | 5 / 70 |
Outcome results
Primary
Estimated Percentage of Participants With Event Free Survival
An event is defined as relapse or transplant-related mortality. Relapse is defined in section 3.3 study protocol.
Time frame: at 2 years
Population: Two ineligible patients on experimental arm excluded from analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Experimental | Estimated Percentage of Participants With Event Free Survival | 45 percentage of participants |
| Control | Estimated Percentage of Participants With Event Free Survival | 54 percentage of participants |
Secondary
Chimerism
Evaluate the relative contribution of resistance by ALL blasts to the donor immune response as a cause of relapse post transplantation.
Time frame: Up to 12 months
Population: We are not able to perform this analysis given the low numbers of blast samples available.
Secondary
Estimated Rate of Acute Graft VS Host Disease (GVHD)
Any grade acute graft vs host disease (defined in APPENDIX II study protocol).
Time frame: At 200 days
Population: 2 ineligible patients on experimental arm excluded from analysis. Definition of Acute GVHD: APPENDIX II: COG STEM CELL COMMITTEE CONSENSUS GUIDELINES FOR ESTABLISHING ORGAN STAGE AND OVERALL GRADE OF ACUTE GRAFT VERSUS HOST DISEASE (GVHD) page 90-96 protocol.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Experimental | Estimated Rate of Acute Graft VS Host Disease (GVHD) | 32 percentage of participants |
| Control | Estimated Rate of Acute Graft VS Host Disease (GVHD) | 49 percentage of participants |
Secondary
Estimated Rate of Overall Chronic Graft VS Host Disease
Chronic graft vs host disease is defined in APPENDIX III of study protocol.
Time frame: At 2 years
Population: 2 ineligible patients on experimental arm excluded from analysis. Definition of Chronic GVHD: APPENDIX III: DEFINING CHRONIC GRAFT VS. HOST DISEASE (FROM BMT CTN MOP SEPT. 2005) on page 97 protocol.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Experimental | Estimated Rate of Overall Chronic Graft VS Host Disease | 22 percentage of participants |
| Control | Estimated Rate of Overall Chronic Graft VS Host Disease | 27 percentage of participants |
Secondary
Estimated Transplant Related Mortality Percentage
Death in a patient who had not relapsed after transplant is defined as transplant-related mortality event.
Time frame: 100 days
Population: 2 ineligible patients on experimental arm excluded from analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Experimental | Estimated Transplant Related Mortality Percentage | 13 percentage of participants |
| Control | Estimated Transplant Related Mortality Percentage | 6 percentage of participants |
Secondary
Rate of Relapses
An event is defined as relapse.
Time frame: At 2 years
Population: 2 ineligible patients on experimental arm excluded from analysis.Testing for recurrent malignancy in the blood, marrow or other sites will be used to assess relapse after transplantation. For the purpose of this study, relapse is defined by either morphological or cytogenetic evidence of ALL consistent with pre-transplant features.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Experimental | Rate of Relapses | 41 percentage of participants |
| Control | Rate of Relapses | 33 percentage of participants |
Secondary
Relative Contribution of ALL Blasts to the Donor Immune Response as a Cause of Relapse Post Transplantation (Correlating Development of aGVHD With Relapse)
An event is defined as relapse; estimated probability of relapse.
Time frame: At 1 year
Population: Number at risk among no aGVHD and number at risk among aGVHD at 1 year. The two treatment regimens were intended to be analyzed together (combined data), as pre-specified in the study protocol, therefore results are not reported for each Arm of study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Experimental | Relative Contribution of ALL Blasts to the Donor Immune Response as a Cause of Relapse Post Transplantation (Correlating Development of aGVHD With Relapse) | Experienced aGVHD, later relapsed | 5 percentage of participants |
| Experimental | Relative Contribution of ALL Blasts to the Donor Immune Response as a Cause of Relapse Post Transplantation (Correlating Development of aGVHD With Relapse) | No aGVHD occurence, relapsed | 24 percentage of participants |
Secondary
Relative Contribution of ALL Blasts to the Donor Immune Response as a Cause of Relapse Pre-Transplantation (MRD)
An event is defined as relapse; relapse risk is reported. Not able to be performed given the low numbers of blast samples available.
Time frame: At 2 months
Population: The two treatment regimens were intended to be analyzed together (combined data), as pre-specified in the study protocol. However, we are not able to perform this analysis given the low numbers of blast samples available.
Secondary
Relative Contribution of Resistance by Acute Lymphoblastic Leukemia (ALL) Blasts to Cytolytic Therapy (e.g., Chemotherapy/Irradiation) as a Cause of Relapse Post-transplantation
An event is defined as relapse or transplant-related mortality.
Time frame: Up to 1 year
Population: We made a large number of xenograft models but were not able to correlate resistance to rapamycin in mice with outcome on the trial with the numbers that we had. For this reason, no specific publications addressing this aim were put forward.