HLA-Nonidentical Stem Cell and Natural Killer Cell Transplantation for Children Less the Two Years of Age With Hematologic Malignancies

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00145626

Enrollment

Registered

2005-09-05

Start date

2004-05-31

Completion date

2016-07-31

Last updated

2017-06-19

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Acute Lymphocytic Leukemia, Acute Myeloid Leukemia, Chronic Myeloid Leukemia, Histiocytosis, Myelodysplasia

Keywords

Stem cell transplantation, Stem cell transplant, Haploidentical transplant

Brief summary

Recent studies of conventional chemotherapy for infants with high-risk hematologic malignancies show that the long-term disease-free survival is low. Although blood and marrow stem cell transplantation using an HLA identical sibling has improved the outcome for these children, less than 25% have this donor source available. Another option is haploidentical transplantation using a partially matched family member donor (i.e. parental donor). Although haploidentical transplantation has proven curative for some patients, this procedure has been hindered by significant complications, primarily regimen-related toxicity including infection and graft versus host disease (GVHD). Building on prior institutional trials, this study will provide patients a haploidentical graft depleted of T lymphocytes using the investigational device, CliniMACS selection system. One week after the transplant procedure, patients will also receive an infusion of additional donor derived white blood cells called Natural Killer (NK) cells in an effort to decrease risks for rejection of the graft, disease relapse, and regimen related toxicity. The primary objective of the study is to evaluate 1 year survival in infants with high risk hematologic malignancies who receive this study treatment.

Detailed description

Secondary objectives for this study include the following: * To estimate the incidence of three transplant-related adverse outcomes (i.e., regimen-related mortality, engraftment failure, and fatal acute GVHD) in the first 100 days after transplantation. * To estimate the incidence of chronic graft-versus-host disease. * To evaluate those factors that affect one-year survival. * To assess the kinetics of lymphohematopoietic reconstitution. * To assess the frequency and clinical relevance of minimal residual disease (MRD) before and after transplantation. * To evaluate the incidence of and risk factors for long-term neurocognitive deficit and organ dysfunction.

Interventions

DRUGChemotherapy and antibodies

Study participants will receive a non-TBI based preparative regimen consisting of Cyclophosphamide, fludarabine, thiotepa, melphalan, and muromonab-CD3 (OKT3) followed by an infusion of a T-lymphocyte depleted haploidentical hematopoietic stem cell graft. Seven days posttransplant, participants will receive an infusion of additional donor derived cells called NK cells.

DEVICEMiltenyi Biotec CliniMACS

Stem cell selection device

PROCEDUREAllogeneic stem cell transplantation

Allogeneic natural killer (NK)cell infusion

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

No minimum to 24 Months

Healthy volunteers

Inclusion criteria

Must have one of the following diagnosis: * AML in remission or relapse (e.g., FAB M7 or biphenotypic leukemia) * High-risk ALL in first remission (e.g., poor responder to prednisone, Ph+ ALL) * ALL beyond first remission * Secondary leukemia * Primary myelodysplasia (including RAEB, RAEB-T, CMML, JCML, and JMML) * Chronic myeloid leukemia * Histiocytoses (including multi-system Langerhans' cell histiocytosis and hemophagocytic lymphohistiocytosis Inclusion criteria Donor research participants * HIV negative (date). * Hepatitis B surface antigen negative (date). * Hepatitis C antibody negative (date). * Syphilis negative (date). * Donor is equal to or greater than 3 on 6 HLA match (date). * Not pregnant (negative pregnancy test). * Not lactating. * At least 18 years of age.

Exclusion criteria

* Patients greater than 24 months of age at the time of transplant. * HLA-identical sibling donor is available. * Cardiac function: shortening fraction \<25%. * Pulse oximetry oxygen saturation \<92% on room air. * Glomerular filtration rate less than 40 ml/min/1.73 m2 (may use Technetium-99 result for GFR). * Direct bilirubin \> 3 mg/dl. * SGPT \> 500 U/L. * Patients with previous allergy to mouse proteins. * Patients with previous allergy to rabbit serum products. * Patients with Down's syndrome

Design outcomes

Primary

Measure	Time frame	Description
One-year Survival	One year after transplant	The one-year survival of infants with high-risk hematologic malignancies who receive a haploidentical transplant procedure using a total body irradiation (TBI)-excluding conditioning regimen followed by an HLA-nonidentical family donor hematopoietic stem cell (HSC) graft depleted of T cells ex vivo using the CliniMACS CD34+ selection system, with a subsequent infusion of donor NK cells purified ex vivo using the CliniMACS CD3+ depletion and CD56+ enrichment system. The Kaplan-Meier estimate for one-year survival is reported.

Secondary

Measure	Time frame	Description
Number of Transplant-Related Adverse Outcomes: Regimen-Related Mortality	100 days post-transplantation	The cumulative incidences of regimen-related mortality will be estimated using method of Kalbfleisch and Prentice.
Number of Transplant-Related Adverse Outcomes: Engraftment Failure	100 days post-transplantation	Engraftment failure is defined as \<10% donor cell chimerism at any time point between 28 and 100 days after transplant with no evidence of disease relapse or requiring stem cell boost.
Number of Transplant-Related Adverse Outcomes: Fatal Acute Graft-Versus Host Disease (GVHD)	100 days post-transplantation	The cumulative incidence estimate for occurrence of fatal acute GVHD by the end of the first 100 days post-transplant was calculated using method of Kalbfleisch and Prentice.
Number of Incidences of Chronic GVHD.	Up to 5 years after transplant	Chronic GVHD was graded according to Seattle Criteria: limited or extensive. Limited is defined as localized skin and/or hepatic dysfunction. Extensive is defined as one or more of the following: * generalized skin involvement * liver histology showing chronic aggressive hepatitis, bridging necrosis or cirrhosis * eye dryness with Schirmer's test \<5 mm wetting * oral: involvement of salivary glands or oral mucosa * other: another target organ involvement
Factors Affecting One-year Survival: Median Age of Donor at HSCT	Up to one year after transplant	Due to small sample size (n=14) and total number of events (n=7), the analysis to check the various factors that affect the one-year survival was not performed (using logistic and cox model).
Factors Affecting One-year Survival: Median Dose of CD34	Up to one year after transplant	Due to small sample size (n=14) and total number of events (n=7), the analysis to check the various factors that affect the one-year survival was not performed (using logistic and cox model).
Factors Affecting One-year Survival: Median Dose of NK Cells	Up to one year after transplant	Due to small sample size (n=14) and total number of events (n=7), the analysis to check the various factors that affect the one-year survival was not performed (using logistic and cox model).
Factors Affecting One-year Survival: Disease Status at HSCT	Up to one year after transplant	Due to small sample size (n=14) and total number of events (n=7), the analysis to check the various factors that affect the one-year survival was not performed (using logistic and cox model).
Factors Affecting One-year Survival: Donor Type	Up to one year after transplant	Due to small sample size (n=14) and total number of events (n=7), the analysis to check the various factors that affect the one-year survival was not performed (using logistic and cox model).
Factors Affecting One-year Survival: Match N/6 HLA Loci	Up to one year after transplant	HLA typing determined the degree of match by looking at 6 different HLA loci. The results indicate the number of the 6 loci that matched for each participant. Due to small sample size (n=14) and total number of events (n=7), the analysis to check the various factors that affect the one-year survival was not performed (using logistic and cox model).
Factors Affecting One-year Survival: Minimal Residual Disease (MRD)	Up to one year after transplant	Detection of leukemia blasts in bone marrow by flow cytometry
Incidence of and Risk Factors for Organ Dysfunction.	Up to 5 Years after transplant	The organ dysfunction will be summarized using summary statistics and assessed in a longitudinal manner and analyzed accordingly.
Incidence of and Risk Factors for Long-term Neurocognitive Deficit.	Up to 5 Years after transplant	The long-term neurocognitive deficit will be summarized using summary statistics and assessed in a longitudinal manner and analyzed accordingly.
Frequency of and Clinical Relevance of Minimal Residual Disease (MRD) Before and After Transplantation	Baseline before HSCT, 1 year post HSCT, and up to 5 years post HSCT	The presence or absence of MRD before and after the bone marrow transplant (BMT) and its frequency distribution will be obtained for each time point separately.
Kinetics of Lymphohematopoietic Reconstitution	From 0-3 months after HSCT through 4-5 years after HSCT	The lymphohematopoietic reconstitution will be summarized using summary statistics and assessed in a longitudinal manner and analyzed accordingly.

Countries

United States

Participant flow

Recruitment details

19 participants and 21 stem cell donors were enrolled between October 2006 and June 2011. The study was temporarily closed to accrual in June 2011 due to unavailability of study drug. The study was formally closed March 2015 because of continued unavailability of study drug. The 21 donors are excluded from this report.

Pre-assignment details

19 stem cell recipients were enrolled, and 5 were excluded. Two participants did not have natural killer cell infusions due to donor was unable to donate enough CD34+ cells or CD56+ cells for infusion, 1 participant became ineligible because they turned 2 years old prior to start of therapy, 1 withdrew and 1 expired.

Participants by arm

Arm	Count
Alive Group of participants who survived to at least one year post HSCT. Study participants received a non-TBI based preparative regimen consisting of Cyclophosphamide, fludarabine, thiotepa, melphalan, and muromonab-CD3 (OKT3) followed by an infusion of a T-lymphocyte depleted haploidentical hematopoietic stem cell graft. Seven days posttransplant, participants received an infusion of additional donor derived cells called natural killer (NK) cells. Stem cells were obtained from donors using the Miltenyi Biotec CliniMACS stem cell selection device.	7
Expired Those participants who did not survive to at least one year post HSCT. Study participants received a non-TBI based preparative regimen consisting of Cyclophosphamide, fludarabine, thiotepa, melphalan, and muromonab-CD3 (OKT3) followed by an infusion of a T-lymphocyte depleted haploidentical hematopoietic stem cell graft. Seven days posttransplant, participants received an infusion of additional donor derived cells called natural killer (NK) cells. Stem cells were obtained from donors using the Miltenyi Biotec CliniMACS stem cell selection device.	7
Total	14

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Death	1
Overall Study	Did not have NK infusions	2
Overall Study	Turned 2 years old before treatment	1
Overall Study	Withdrawal by Subject	1

Baseline characteristics

Characteristic	Alive	Expired	Total
Age, Continuous	1.0 years	0.8 years	0.9 years
Race/Ethnicity, Customized Black	2 Participants	2 Participants	4 Participants
Race/Ethnicity, Customized Other	1 Participants	1 Participants	2 Participants
Race/Ethnicity, Customized White	4 Participants	4 Participants	8 Participants
Sex: Female, Male Female	3 Participants	3 Participants	6 Participants
Sex: Female, Male Male	4 Participants	4 Participants	8 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	— / —
other Total, other adverse events	16 / 16
serious Total, serious adverse events	15 / 16

Outcome results

Primary

One-year Survival

The one-year survival of infants with high-risk hematologic malignancies who receive a haploidentical transplant procedure using a total body irradiation (TBI)-excluding conditioning regimen followed by an HLA-nonidentical family donor hematopoietic stem cell (HSC) graft depleted of T cells ex vivo using the CliniMACS CD34+ selection system, with a subsequent infusion of donor NK cells purified ex vivo using the CliniMACS CD3+ depletion and CD56+ enrichment system. The Kaplan-Meier estimate for one-year survival is reported.

Time frame: One year after transplant

Arm	Measure	Value (NUMBER)
Study Participants	One-year Survival	50 percentage of participants

Secondary

Factors Affecting One-year Survival: Disease Status at HSCT

Due to small sample size (n=14) and total number of events (n=7), the analysis to check the various factors that affect the one-year survival was not performed (using logistic and cox model).