Accelerated Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Acute Biphenotypic Leukemia, Acute Leukemia of Ambiguous Lineage, Acute Undifferentiated Leukemia, Adult Acute Lymphoblastic Leukemia in Remission, Adult Acute Myeloid Leukemia in Remission, Blast Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Childhood Acute Lymphoblastic Leukemia in Remission, Childhood Acute Myeloid Leukemia in Remission, Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Myelodysplastic Syndrome With Excess Blasts-1, Myelodysplastic Syndrome With Excess Blasts-2, Recurrent Adult Acute Lymphoblastic Leukemia, Recurrent Adult Acute Myeloid Leukemia, Recurrent Childhood Acute Lymphoblastic Leukemia, Recurrent Childhood Acute Myeloid Leukemia, Refractory Adult Acute Lymphoblastic Leukemia, Refractory Childhood Acute Lymphoblastic Leukemia
Conditions
Brief summary
This phase II trial studies how well T cell depleted donor peripheral blood stem cell transplant works in preventing graft-versus-host disease in younger patients with high risk hematologic malignancies. Giving chemotherapy and total-body irradiation before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Removing a subset of the T cells from the donor cells before transplant may stop this from happening.
Detailed description
OUTLINE: CONDITIONING REGIMEN: Patients undergo total body irradiation (TBI) twice daily (BID) on days -10 to -7, receive thiotepa intravenously (IV) over 4 hours on days -6 and -5 and fludarabine phosphate IV over 30 minutes on days -6 to -2. TRANSPLANT: Patients undergo CD34+ enriched, CD45RA+ T cell-depleted allogeneic PBSCT on day 0. POST-TRANSPLANT IMMUNOSUPPRESSION: Patients receive tacrolimus IV continuously or orally (PO) every 12 hours beginning on day -1 and continuing through day 50 with taper. Patients also receive methotrexate IV on days 1, 3, 6, and 11. After completion of study treatment, patients are followed up for up to 5 years.
Interventions
Undergo CD45RA+ T cell-depleted allogeneic peripheral blood stem cell transplant
Given IV
Correlative studies
Given IV
Undergo CD45RA+ T cell-depleted allogeneic peripheral blood stem cell transplant
Undergo CD45RA+ T cell-depleted allogeneic peripheral blood stem cell transplant
Given IV or PO
Given IV
Undergo TBI
Sponsors
Study design
Eligibility
Inclusion criteria
* Patients who are considered appropriate candidates for allogeneic hematopoietic stem cell transplantation and have one of the following diagnoses: * Acute lymphocytic leukemia in first or subsequent remission * Acute myeloid leukemia in first or subsequent remission * Acute lymphocytic leukemia in relapse or primary refractory disease with a circulating blast count of no more than 10,000/mm\^3 * Acute myeloid leukemia in relapse or primary refractory disease with a circulating blast count of no more than 10,000/mm\^3 * Refractory anemia with excess blasts (RAEB-1 and RAEB-2) * Chronic myelogenous leukemia with a history of accelerated phase or blast crisis * Other acute leukemia (including but not limited to 'biphenotypic', 'undifferentiated' or 'ambiguous lineage' acute leukemia) * Patient with a human leukocyte antigen (HLA)-identical (HLA-A, B, C, and ribonucleic acid \[RNA\] binding motif protein 45 \[DRB1\] molecularly matched) unrelated donor or related donor capable of donating PBSC * DONOR: HLA-matched unrelated donors (HLA-A, B, C, and DRB1 matched based on high-resolution typing) capable and willing to donate PBSC * DONOR: HLA-matched related donors \>= 18 years and capable and willing to donate PBSC
Exclusion criteria
* Patients with central nervous system (CNS) involvement refractory to intrathecal chemotherapy and/or standard cranial-spinal radiation * Patients on other experimental protocols for prevention of acute GVHD * Patients who weigh \>= 70 kg must be discussed with the principal investigator prior to enrolling on the protocol * Patients who are human immunodeficiency virus positive (HIV+) * Patients with uncontrolled infections for whom myeloablative hematopoietic stem cell transplant (HCT) is considered contraindicated by the consulting infectious disease physician (upper respiratory tract viral infection does not constitute an uncontrolled infection in this context) * Creatinine \> 1.5 mg/dl * Cardiac ejection fraction \< 45% * Patients who can perform pulmonary function tests will be excluded if they have a diffusing capacity of the lung for carbon monoxide (DLCO) (corrected for hemoglobin) of \< 60% predicted; patients who are unable to perform pulmonary function tests (for example, due to young age and/or developmental status) will be excluded if the oxygen (O2) saturation is \< 92% on room air * Patients who have liver function test (LFTs) (including total bilirubin, aspartate aminotransferase \[AST\] and alanine aminotransferase \[ALT\]) \>= twice the upper limit of normal should be evaluated by a gastrointestinal (GI) physician unless there is a clear precipitating factor (such as an azole, methotrexate, Bactrim or another drug); if the GI physician considers that HCT on protocol 2660 is contraindicated for that patient the patient will be excluded from the protocol; patients with Gilbert's syndrome and no other known liver function abnormality and patients with reversible drug-related transaminitis do not necessarily require GI consultation and may be included on the protocol * Patients with a life expectancy \< 3 months from co-existing disease other than the leukemia or RAEB * Patients who are pregnant or breast-feeding * Fertile patients of child bearing age unwilling to use contraception during and for 12 months post-transplant * Patients with a significant other medical conditions that would make them unsuitable for transplant * Patients with a known hypersensitivity to tacrolimus * DONOR: Donors who are HIV-1, HIV-2, human T-lymphotropic virus (HTLV)-1, HTLV-2 seropositive or with active hepatitis B or hepatitis C virus infection * DONOR: Donors who fail eligibility requirements for donation of cells or tissue per section 21 Code of Federal Regulations (CFR) 1271 for donation of a HCT/product (P) will be excluded unless use of the cells complies with 21 CFR 1271.65(b)(iii) (urgent medical need) or with 21 CFR 1271.65(b)(i) (allogeneic use in a first-degree or second-degree relative) * DONOR: Unrelated donors donating outside of the United States of America (USA) or Germany
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Graft Failure | Up to 5 years | Graft failure defined as failure to reach ANC of \>500/uL for 3 consecutive days by day 28, or irreversible decrease in ANC to \<100 after an established donor graft. A reduction in ANC as result of relapse is not considered graft failure |
| Time to Discontinuation of Systemic Immunosuppression | 5 years post transplant | Measure the number of days to discontinuation of systemic immunosuppression (both including and excluding calcineurin inhibitors) in pediatric recipients of CD45RA+ T cell-depleted PBSCT. Possible outcomes range from no systemic immunosuppression (best outcome) to 5 years on immunosuppression (poor outcome) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to ANC of > 1,000/uL | Up to 5 years | Time (in days) to ANC of \> 1,000/uL, counted as the first of three consecutive days post-transplant |
| Time to ANC of > 500/uL | Up to 5 years | Time (in days) to ANC of \> 500/uL, counted as the first of three consecutive days post-transplant |
| Occurrence of Chronic GHVD Meeting NIH Criteria and Requiring Systemic Pharmacological Immunosuppression | Up to 5 years | Number of patients with chronic GVHD defined using NIH criteria. Incidents requiring only calcineurin inhibitors will not be counted. If patients do not develop cGVHD after transplant but then relapse and then receive a donor lymphocyte infusion or antigen specific T cells as treatment, they will no longer be evaluable for the cGVHD endpoint. |
| Acute GVHD Grade III-IV | Up to day 100 | Number of patients with acute GVHD grade III-IV |
| Time to Platelet Count > 50,000/uL for 3 Days Without Transfusion | Up to 5 years | Number of days post-transplant without transfusion where platelet count is \>50,000/uL. Measured as the first of three days |
| Steroid Refractory Acute GVHD | Up to day 100 | Presence of steroid refractory acute GVHD within the first 100 days post transplant |
| Relapse Post-transplant | Up to 5 years | Relapse defined by the presence of malignant cells in marrow, peripheral blood, or extramedullary sites by histopathology |
| Transplant Related Mortality | Up to 5 years | Transplant related mortality defined as mortality in any patient for whom there has not been a diagnosis of relapse |
| Use of Additional Immune Suppressive Agents to Treat Chronic GVHD | Up to 5 years | Use of additional immune suppressive agents to treat chronic GVHD other than first line therapy. First line therapy is considered prednisone and tacrolimus/cyclosporin. |
| Acute GVHD Grades II-IV | Up to day 100 | Number of patients with acute GVHD grades II-IV |
| Time to Platelet Count > 20,000/uL for 3 Days Without Transfusion | Up to 5 years | Number of days post transplant until platelet count is \>20,000/uL for three consecutive days without transfusion, counted as the first of three days |
Countries
United States
Participant flow
Recruitment details
Participants were recruited based on referral for Hematopoietic Cell transplant at Fred Hutchinson Cancer Center between March 2014 and January 2017. The first participant was enrolled on April 10, 2014 and the last participant was enrolled on January 27, 2017.
Pre-assignment details
Of the 20 patients enrolled, all 20 met inclusion criteria and went forward to be treated on the study.
Participants by arm
| Arm | Count |
|---|---|
| Overall Study Participants All participants in single arm study received CD45RA+ T cell depletion PBSC transplant and IV Methotrexate and tacrolimus for GVHD prophylaxis (Day -1 to Day 50, then tapered from day 50) | 20 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 4 |
Baseline characteristics
| Characteristic | Overall Study Participants |
|---|---|
| Age, Categorical <=18 years | 20 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 19 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 19 Participants |
| Region of Enrollment United States | 20 participants |
| Sex: Female, Male Female | 10 Participants |
| Sex: Female, Male Male | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 4 / 20 |
| other Total, other adverse events | 20 / 20 |
| serious Total, serious adverse events | 0 / 20 |
Outcome results
Graft Failure
Graft failure defined as failure to reach ANC of \>500/uL for 3 consecutive days by day 28, or irreversible decrease in ANC to \<100 after an established donor graft. A reduction in ANC as result of relapse is not considered graft failure
Time frame: Up to 5 years
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Overall Study Participants | Graft Failure | Fail to engraft by D28 | 0 Participants |
| Overall Study Participants | Graft Failure | Fail to maintain ANC >100 for 5 years | 1 Participants |
Time to Discontinuation of Systemic Immunosuppression
Measure the number of days to discontinuation of systemic immunosuppression (both including and excluding calcineurin inhibitors) in pediatric recipients of CD45RA+ T cell-depleted PBSCT. Possible outcomes range from no systemic immunosuppression (best outcome) to 5 years on immunosuppression (poor outcome)
Time frame: 5 years post transplant
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Overall Study Participants | Time to Discontinuation of Systemic Immunosuppression | Discontinuation (or never started) prednisone | 106 Days |
| Overall Study Participants | Time to Discontinuation of Systemic Immunosuppression | Discontinuation of systemic immunosuppression (including calcineurin inhibitors) | 349 Days |
Acute GVHD Grade III-IV
Number of patients with acute GVHD grade III-IV
Time frame: Up to day 100
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Overall Study Participants | Acute GVHD Grade III-IV | Grade III acute GVHD | 2 Participants |
| Overall Study Participants | Acute GVHD Grade III-IV | Grade IV acute GVHD | 0 Participants |
Acute GVHD Grades II-IV
Number of patients with acute GVHD grades II-IV
Time frame: Up to day 100
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Overall Study Participants | Acute GVHD Grades II-IV | Grade II acute GVHD | 15 Participants |
| Overall Study Participants | Acute GVHD Grades II-IV | Grade III acute GVHD | 2 Participants |
| Overall Study Participants | Acute GVHD Grades II-IV | Grade IV acute GVHD | 0 Participants |
Occurrence of Chronic GHVD Meeting NIH Criteria and Requiring Systemic Pharmacological Immunosuppression
Number of patients with chronic GVHD defined using NIH criteria. Incidents requiring only calcineurin inhibitors will not be counted. If patients do not develop cGVHD after transplant but then relapse and then receive a donor lymphocyte infusion or antigen specific T cells as treatment, they will no longer be evaluable for the cGVHD endpoint.
Time frame: Up to 5 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Overall Study Participants | Occurrence of Chronic GHVD Meeting NIH Criteria and Requiring Systemic Pharmacological Immunosuppression | 0 Participants |
Relapse Post-transplant
Relapse defined by the presence of malignant cells in marrow, peripheral blood, or extramedullary sites by histopathology
Time frame: Up to 5 years
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Overall Study Participants | Relapse Post-transplant | Relapse in first 100 days | 0 Participants |
| Overall Study Participants | Relapse Post-transplant | Relapse between day 101 to 6 months | 0 Participants |
| Overall Study Participants | Relapse Post-transplant | Relapse between 6 months to 1 year | 2 Participants |
| Overall Study Participants | Relapse Post-transplant | Relapse between 1 to 5 years | 1 Participants |
| Overall Study Participants | Relapse Post-transplant | Total relapse in first 5 years | 3 Participants |
Steroid Refractory Acute GVHD
Presence of steroid refractory acute GVHD within the first 100 days post transplant
Time frame: Up to day 100
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Overall Study Participants | Steroid Refractory Acute GVHD | 0 Participants |
Time to ANC of > 1,000/uL
Time (in days) to ANC of \> 1,000/uL, counted as the first of three consecutive days post-transplant
Time frame: Up to 5 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Overall Study Participants | Time to ANC of > 1,000/uL | 23 Days |
Time to ANC of > 500/uL
Time (in days) to ANC of \> 500/uL, counted as the first of three consecutive days post-transplant
Time frame: Up to 5 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Overall Study Participants | Time to ANC of > 500/uL | 20.5 Days |
Time to Platelet Count > 20,000/uL for 3 Days Without Transfusion
Number of days post transplant until platelet count is \>20,000/uL for three consecutive days without transfusion, counted as the first of three days
Time frame: Up to 5 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Overall Study Participants | Time to Platelet Count > 20,000/uL for 3 Days Without Transfusion | 19.5 Days |
Time to Platelet Count > 50,000/uL for 3 Days Without Transfusion
Number of days post-transplant without transfusion where platelet count is \>50,000/uL. Measured as the first of three days
Time frame: Up to 5 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Overall Study Participants | Time to Platelet Count > 50,000/uL for 3 Days Without Transfusion | 23 Days |
Transplant Related Mortality
Transplant related mortality defined as mortality in any patient for whom there has not been a diagnosis of relapse
Time frame: Up to 5 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Overall Study Participants | Transplant Related Mortality | 3 Participants |
Use of Additional Immune Suppressive Agents to Treat Chronic GVHD
Use of additional immune suppressive agents to treat chronic GVHD other than first line therapy. First line therapy is considered prednisone and tacrolimus/cyclosporin.
Time frame: Up to 5 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Overall Study Participants | Use of Additional Immune Suppressive Agents to Treat Chronic GVHD | 0 Immunosuppressive agents |