Leukemia, Solid Tumors
Conditions
Keywords
Recurrent or Refractory Leukemia or Solid Tumors in Pediatrics
Brief summary
This study will assess the feasibility of utilizing a reduced intensity conditioning regimen, in the setting of haploidentical transplantation, for patients with recurrent acute lymphoblastic leukemia (ALL), AML and high risk or refractory solid tumors. In addition, the feasibility and safety of administering post-transplant NK cell infusions will be evaluated. Data obtained from this study will help determine the efficacy of allogeneic HSCT in the treatment of pediatric sarcomas and add to the small body of literature utilizing haploidentical HSCT to treat acute leukemia in pediatric patients. This study will also further elucidate the role of NK cells in mediating a graft vs. tumor effect in allogeneic HSCT. The main benefit to society is that this study will explore a novel therapy for children with highly refractory cancer who are felt to be incurable with conventional approaches. If feasibility is demonstrated, and there is evidence of anti-tumor activity, then this will open up a new area of clinical research to better define the efficacy of this approach for specific childhood malignancies.
Interventions
DEVICEClinimacs Cell Separation System
Depletion of T-cells
Methylprednisolone, Equine ATG, Cyclosporine, Fludarabine, Melphalan, Thiotepa and Rituximab.
OTHERDLI
NK Cell selected DLI
Sponsors
Miltenyi Biomedicine GmbH
University of Wisconsin, Madison
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Months to 25 Years
Healthy volunteers
No
Inclusion criteria
* Solid tumors that have failed auto transplant or are ineligible to receive auto transplant * Relapsed AML in 1st relapse or 2nd or 3rd CR * Relapsed ALL if they fail to attain an initial remission or if they relapse within 1 year following the discontinuation of chemotherapy. * Greater than or equal to 6 months and \<26 years old * Suitable haploidentical donor available
Exclusion criteria
* Leukemia with \>25% blasts in bone marrow at the time of admission to the HSCT unit. * Serum bilirubin \>3 mg/dl * GFR \<40 ml/min/1.73 mw * Cardiac left ventricular ejection fraction \<40% * HIV+ * Pregnant
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Grade III or IV GVHD | Day 100 | Skin Grade III: Stage 0-4 GVHD, where 0 is no rash and 4 is generalized erythroderma with bullous formation and/or with desquamation Grade IV: Stage 4 GVHD, generalized erythroderma with bullous formation and/or with desquamation GI (diarrhea) Grade III: Stage 2-4 GVHD, where 2 is \> 1000 mL/day but ≤ 1500 mL/day or 556-833 mL/m2, and 4 is severe abdominal pain +/- ileus or stool with frank blood or melena Grade IV: Stage 0-4 GVHD, where 0 is \< 500 mL/day or 280 mL/m2, and 4 is severe abdominal pain +/- ileus or stool with frank blood or melena Overall: Grade III: Grade III Skin and/or GI as well as bilirubin 3.1-15 mg/dl Grade IV: Grade IV Skin and/or GI as well as bilirubin \> 15 mg/dl |
| Engraftment Failure | 28 days | Utilize non-myeloablative conditioning regimen in the haploidentical transplant setting. Primary engraftment failure: failure to achieve ANC of ≥500/uL prior to day +28 Late engraftment failure: Initial engraftment achieved with ANC ≥500/uL by day +28 followed by loss of graft Autologous Cells Infused: achieved hematologic recovery following infusions of autologous stem cells Second Haploidentical Transplant: re-transplantation utilizing an alternative haploidentical donor |
| Number of Days Until Engraftment Criteria Were Met | 28 days | Utilize non-myeloablative conditioning regimen in the haploidentical transplant setting. Engraftment is defined as achieving an absolute neutrophil count ≥ 500 by 28 days post-transplant; platelets and red blood cells will also be measured up to 28 days: * Neutrophils: ≥500/uL for 3 days * Platelets: ≥20 K/uL for 3 days without transfusion * Red blood cells: the date of the last RBC transfusion after achieving transfusion independence Results are reported as number of days until engraftment criteria was met, per neutrophil, platelet and red blood cell measurements, above. |
| Mortality Rate | 100 days post-transplant | Mortality rate at 100 days post-transplant. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Association Between Parental KIR Genotypes and NK Cell Cytotoxicities | Day 60 | NK cells express killer-cell immunoglobulin-like receptors (KIR) and have cytotoxic activity. The association between NK cell cytotoxicity over time and KIR genotypes will be examined. Blood samples will be collected at months 1, 2, 3, 6, 9, and 12. |
| Analysis of NK Cell KIR Expression Over Time | Up to 12 months | NK cell KIR expression over time will be examined. Blood samples will be collected at months 1, 2, 3, 6, 9, and 12. |
| NK Expression Levels | Up to 12 months | Natural Killer (NK) cell expression levels will be explored. Blood samples will be collected at months 1, 2, 3, 6, 9, and 12. |
Countries
United States
Participant flow
Recruitment details
This study enrolled patients with relapsed acute leukemia and very high-risk solid tumors. The last subject was enrolled in October 2013.
Participants by arm
| Arm | Count |
|---|---|
| Haploidentical Transplant With NK Cell Infusion Patients underwent a standard pre-transplant evaluation, but will also had blood drawn to evaluate their HLA class I killer immunoglobulin-like receptor (KIR) ligand typing. Parents underwent KIR genotyping and phenotyping, and a donor was selected based on which parent showed the greatest degree of KIR receptor-ligand mismatching. When the donor had been selected he/she underwent a peripheral blood stem cell (PBSC) collection utilizing G-CSF and GM-CSF for stem cell mobilization. The PBSC collection was performed utilizing standard procedures. The PBSC was then be processed in the UW BMT Laboratory in order to deplete the graft of T cells. This was accomplished using the CliniMACS cell separation system. T cell depletion is a standard procedure for patients receiving haploidentical stem cell grafts. The resulting stem cell product were analyzed for T cell, stem cell and NK cell content.
Clinimacs Cell Separation System: Depletion of T-cells | 9 |
| Total | 9 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Engraftment Failure | 3 |
Baseline characteristics
| Characteristic | Haploidentical Transplant With NK Cell Infusion |
|---|---|
| Age, Categorical <=18 years | 9 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 | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 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 | 1 Participants |
| Race (NIH/OMB) White | 8 Participants |
| Region of Enrollment United States | 9 participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 9 |
| serious Total, serious adverse events | 8 / 9 |
Outcome results
Primary
Engraftment Failure
Utilize non-myeloablative conditioning regimen in the haploidentical transplant setting. Primary engraftment failure: failure to achieve ANC of ≥500/uL prior to day +28 Late engraftment failure: Initial engraftment achieved with ANC ≥500/uL by day +28 followed by loss of graft Autologous Cells Infused: achieved hematologic recovery following infusions of autologous stem cells Second Haploidentical Transplant: re-transplantation utilizing an alternative haploidentical donor
Time frame: 28 days
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Haploidentical Transplant With NK Cell Infusion | Engraftment Failure | Primary Engraftment Failure | 2 participants |
| Haploidentical Transplant With NK Cell Infusion | Engraftment Failure | Late Engraftment Failure | 1 participants |
| Haploidentical Transplant With NK Cell Infusion | Engraftment Failure | Autologous Cells Infused | 2 participants |
| Haploidentical Transplant With NK Cell Infusion | Engraftment Failure | Second Haploidentical Transplant | 1 participants |
Primary
Grade III or IV GVHD
Skin Grade III: Stage 0-4 GVHD, where 0 is no rash and 4 is generalized erythroderma with bullous formation and/or with desquamation Grade IV: Stage 4 GVHD, generalized erythroderma with bullous formation and/or with desquamation GI (diarrhea) Grade III: Stage 2-4 GVHD, where 2 is \> 1000 mL/day but ≤ 1500 mL/day or 556-833 mL/m2, and 4 is severe abdominal pain +/- ileus or stool with frank blood or melena Grade IV: Stage 0-4 GVHD, where 0 is \< 500 mL/day or 280 mL/m2, and 4 is severe abdominal pain +/- ileus or stool with frank blood or melena Overall: Grade III: Grade III Skin and/or GI as well as bilirubin 3.1-15 mg/dl Grade IV: Grade IV Skin and/or GI as well as bilirubin \> 15 mg/dl
Time frame: Day 100
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Haploidentical Transplant With NK Cell Infusion | Grade III or IV GVHD | Grade III GVHD - Skin | 3 participants |
| Haploidentical Transplant With NK Cell Infusion | Grade III or IV GVHD | Grade IV GVHD - GI | 2 participants |
| Haploidentical Transplant With NK Cell Infusion | Grade III or IV GVHD | Grade III GVHD - GI | 1 participants |
| Haploidentical Transplant With NK Cell Infusion | Grade III or IV GVHD | Overall Grade III GVHD | 2 participants |
| Haploidentical Transplant With NK Cell Infusion | Grade III or IV GVHD | Overall Grade IV GVHD | 2 participants |
Primary
Mortality Rate
Mortality rate at 100 days post-transplant.
Time frame: 100 days post-transplant
Population: Death Prior to Day +100
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Haploidentical Transplant With NK Cell Infusion | Mortality Rate | 1 participants |
Primary
Number of Days Until Engraftment Criteria Were Met
Utilize non-myeloablative conditioning regimen in the haploidentical transplant setting. Engraftment is defined as achieving an absolute neutrophil count ≥ 500 by 28 days post-transplant; platelets and red blood cells will also be measured up to 28 days: * Neutrophils: ≥500/uL for 3 days * Platelets: ≥20 K/uL for 3 days without transfusion * Red blood cells: the date of the last RBC transfusion after achieving transfusion independence Results are reported as number of days until engraftment criteria was met, per neutrophil, platelet and red blood cell measurements, above.
Time frame: 28 days
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Haploidentical Transplant With NK Cell Infusion | Number of Days Until Engraftment Criteria Were Met | Neutrophils | 18 days |
| Haploidentical Transplant With NK Cell Infusion | Number of Days Until Engraftment Criteria Were Met | Platelets | 16 days |
| Haploidentical Transplant With NK Cell Infusion | Number of Days Until Engraftment Criteria Were Met | Red Blood Cells | 16 days |
Secondary
Analysis of NK Cell KIR Expression Over Time
NK cell KIR expression over time will be examined. Blood samples will be collected at months 1, 2, 3, 6, 9, and 12.
Time frame: Up to 12 months
Population: Blood samples were not collected uniformly as many patients developed GVHD, requiring treatment with steroids. Once steroids were initiated the results of this testing became uninterpretable. No data was collected towards this outcome measure.
Secondary
Association Between Parental KIR Genotypes and NK Cell Cytotoxicities
NK cells express killer-cell immunoglobulin-like receptors (KIR) and have cytotoxic activity. The association between NK cell cytotoxicity over time and KIR genotypes will be examined. Blood samples will be collected at months 1, 2, 3, 6, 9, and 12.
Time frame: Day 60
Population: Blood samples were not collected uniformly as many patients developed GVHD, requiring treatment with steroids. Once steroids were initiated the results of this testing became uninterpretable. No data was collected towards this outcome measure.
Secondary
NK Expression Levels
Natural Killer (NK) cell expression levels will be explored. Blood samples will be collected at months 1, 2, 3, 6, 9, and 12.
Time frame: Up to 12 months
Population: Blood samples were not collected uniformly as many patients developed GVHD, requiring treatment with steroids. Once steroids were initiated the results of this testing became uninterpretable. No data was collected towards this outcome measure.