Acute Erythroid Leukemia, Acute Lymphoblastic Leukemia, Acute Megakaryoblastic Leukemia, Acute Myeloid Leukemia, Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Hematopoietic and Lymphoid Cell Neoplasm, HIV Infection, Myelodysplastic Syndrome, Myelodysplastic Syndrome With Excess Blasts, Non-Hodgkin Lymphoma, Refractory Anemia
Conditions
Brief summary
This phase II trial studies the side effects of a cord blood transplant using dilanubicel and to see how well it works in treating patients with human immunodeficiency virus (HIV) positive hematologic (blood) cancers. After a cord blood transplant, the immune cells, including white blood cells, can take a while to recover, putting the patient at increased risk of infection. Dilanubicel consists of blood stem cells that help to produce mature blood cells, including immune cells. Drugs used in chemotherapy, such as fludarabine, cyclophosphamide, and thiotepa, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Total body irradiation is a type of whole-body radiation. Giving chemotherapy and total-body irradiation before a cord blood transplant with dilanubicel may help to kill any cancer cells that are in the body and make room in the patient's bone marrow for new stem cells to grow and reduce the risk of infection.
Detailed description
OUTLINE: Patients are assigned to 1 of 2 regimens. REGIMEN A: Patients receive fludarabine intravenously (IV) over 30 minutes on days -8 to -6, cyclophosphamide IV on days -7 to -6, and undergo total body irradiation (TBI) twice daily (BID) on days -4 to -1. Patients then undergo umbilical cord blood transplant on day 0. Between 4-24 hours after transplant completion, patients receive dilanubicel IV over 5-10 minutes in the absence of disease progression or unacceptable toxicity. REGIMEN B: Patients receive fludarabine IV over 30-60 minutes on days -6 to -2, cyclophosphamide IV on day -6, thiotepa IV over 4 hours on days -5 to -4, and undergo TBI once daily (QD) on days -2 to -1. Patients then undergo umbilical cord blood transplant on day 0. Between 4-24 hours after transplant completion, patients receive dilanubicel IV over 5-10 minutes in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 28, 80, and 180 days, and then at 1 and 2 years.
Interventions
DRUGFludarabine
Given IV
DRUGCyclophosphamide
Given IV
DRUGThiotepa
Given IV
RADIATIONTotal-Body Irradiation
Undergo TBI
PROCEDUREUmbilical Cord Blood Transplantation
Undergo UCBT
BIOLOGICALDilanubicel
Given IV
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Fred Hutchinson Cancer Center
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Months to 65 Years
Healthy volunteers
No
Inclusion criteria
* \>= 6 months to =\< 65 years * Treatment with combination antiretroviral therapy (cART) for at least 1 month before enrollment * Viral load \< 5000 copies/ml plasma on cART * Disease criteria * Acute myeloid leukemia * High risk in first complete remission (CR1), \>= 2 cycles to obtain complete remission (CR), erythroblastic or megakaryocytic leukemia; \>= in second complete remission (CR2) * All patients must be in CR as defined by hematologic recovery and \< 5% blasts by morphology within the bone marrow and a cellularity of \>= 15% * Patients for whom adequate marrow/biopsy specimens cannot be obtained to determine remission status by morphologic assessment, but have fulfilled criteria of remission by flow cytometry, recovery of peripheral blood counts with no circulating blasts, and/or normal cytogenetics (if applicable) may still be eligible. Specimen for morphologic assessment, including possible repeat procedures will be obtained (as possible). These patients must be discussed with the lead principal investigator, Filippo Milano prior to enrollment * Acute lymphoblastic leukemia * High risk CR1 (for example, but not limited to: t(9;22), t(1;19), t(4;11) or other mixed-lineage leukemia \[MLL\] rearrangements, hypodiploid); greater than 1 cycle to obtain CR; \>= CR2 * All patients must be in CR as defined by hematologic recovery and \< 5% blasts by morphology within the bone marrow and a cellularity of \>= 15% * Patients in which adequate marrow/biopsy specimens cannot be obtained to determine remission status by morphologic assessment, but have fulfilled criteria of remission by flow cytometry, recovery of peripheral blood counts with no circulating blasts, and/or normal cytogenetics (if applicable) may still be eligible. Specimen for morphologic assessment, including possible repeat procedures will be obtained (as possible). These patients must be discussed with the lead principal investigator, Filippo Milano prior to enrollment * Chronic myelogenous leukemia excluding refractory blast crisis. To be eligible in first chronic phase (CP1) patient must have failed or be intolerant to imatinib mesylate * Myelodysplasia (MDS) International Prognostic Scoring System (IPSS) intermediate (Int)-2 or high risk (i.e., refractory anemia with excess blasts \[RAEB\], refractory anemia with excess blasts in transformation \[RAEBt\]) or refractory anemia with severe pancytopenia or high-risk cytogenetics. Blasts must be \< 10% by a representative bone marrow aspirate morphology * Other hematologic malignancy such as non-Hodgkin lymphomas. Fred Hutch site: These patients must be presented at Patient Care Conference (PCC) prior to enrollment, given potential competing eligibility on auto-transplant protocols. Participating centers: These patients must be discussed with the lead principal investigator, Filippo Milano prior to enrollment * Karnofsky (\>= 16 years old) \>= 70% * Lansky (\< 16 years old) \>= 50% * Adults: Calculated creatinine clearance must be \> 60 mL and serum creatinine =\< 2 mg/dL * Children (\< 18 years old): Calculated creatinine clearance must be \> 60 mL/min * Total serum bilirubin must be \< 3 mg/dL * Transaminases must be \< 3 x the upper limit of normal * Diffusion capacity of the lung for carbon monoxide (DLCO) corrected \> 50% normal or for pediatric patients in whom DLCO cannot be measured has adequate pulmonary function * Left ventricular ejection fraction \> 45% OR * Shortening fraction \> 26% * Ability to understand and the willingness to sign a written informed consent document (adult subject or parent/legal guardian of minor subject)
Exclusion criteria
* Uncontrolled viral or bacterial infection at the time of study enrollment * Active or recent (prior 6 month) invasive fungal infection without infectious disease (ID) consult and approval * Pregnant or breastfeeding * Prior myeloablative transplant within the last 6 months * Extensive prior therapy including \> 12 months alkylator therapy or \> 6 months alkylator therapy with extensive radiation * Central nervous system (CNS) leukemic involvement not clearing with intrathecal chemotherapy. Diagnostic lumbar puncture to be performed
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Primary Graft Failure Rejection | Up to day 35 post-transplant | Will be defined by no neutrophil recovery by day 45 (regardless of donor chimerism) or autologous recovery (neutrophil recovery but \< 10% donor chimerism in blood and bone marrow) by day 36. This outcome was originally intended to be assessed for per the aforementioned definitions, but was only able to be assessed through 35 days post-transplant. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Median Number of Days Post-Transplant to Neutrophil Recovery Occurred | Up to Day 35 post-transplant | Neutrophil recovery is defined as the first day of 2 consecutive days of absolute neutrophil count \>= 500 after the first post-cord blood transplant nadir. This outcome was originally intended to be assessed for up to 45 days post-transplant, but was only able to be assessed through 35 days post-transplant. |
| Platelet Engraftment | 35 days post-transplant | Will be defined as the first day of a platelet count \> 20,000/ul with subsequent transfusions for 7 days. This outcome was originally intended to be assessed for up to 2 years post-transplant, but was only able to be assessed through 35 days post-transplant. |
| Incidence of Severe (Grades III-IV) Acute Graft Versus Host Disease (GVHD) | 35 days post-transplant | Will be defined by the 2014 National Institutes of Health (NIH) criteria. This outcome was originally intended to be assessed for up to 2 years post-transplant, but was only able to be assessed through 35 days post-transplant. |
| Incidence of Chronic GVHD | 35 days post-transplant | Will be defined by the 2014 NIH criteria. This outcome was originally intended to be assessed for up to 2 years post-transplant, but was only able to be assessed through 35 days post-transplant. |
| Incidence of Non-relapse Mortality | 35 days post-transplant | Will be defined as death without a prior relapse. This outcome was originally intended to be assessed for up to 180 days post-transplant, but was only able to be assessed through 35 days post-transplant. |
| Incidence of Infusion Toxicities | Within the first 24 hours after infusion | Defined as Common Terminology Criteria for Adverse Events version 5.0 grade \>= 3 events. |
| Immune Homeostasis | Up to 2 years | Concentration of immunity cells per microliters after transplant |
| Immune Reconstitution | Up to 2 years | Concentration of immunity cells per microliters after transplant |
| Change in HIV-1 Induced Inflammatory Immune Responses | Up to 2 years | HIV viral load by PCR (copies per milliliter; mL) |
| HIV Rebound Following Antiretroviral Therapy (ART) Cessation | Up to 2 years | Count of participants with HIV rebound, measured by HIV viral load by PCR (copies per milliliter; mL) |
| Viral Kinetics Following ART Cessation | Up to 2 years | HIV viral load by PCR (copies per milliliter; mL) |
| Human Immunodeficiency Virus (HIV) Plasma Viral Load | Baseline and weekly to 35 days post-transplant | Assess CCR5Δ32 cord blood stem cell engraftment and its effect on biomarkers of HIV-1 infection, including plasma viral load and replication-competent reservoirs, as well as in gut and other sites (if tissue samples are available). This outcome was originally intended to be assessed weekly for up to 2 years post-transplant, but was only able to be assessed through 35 days post-transplant. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Regimen A (Fludarabine, Cyclophosphamide, TBI, Followed by Unmanipulated Cord Blood and Dilanubicel) Patients receive fludarabine IV over 30 minutes on days -8 to -6, cyclophosphamide IV on days -7 to -6, and undergo TBI BID on days -4 to -1 (totaling 1320 cGy). Patients then undergo umbilical cord blood transplant on day 0. Between 4-24 hours after transplant completion, patients receive dilanubicel IV over 5-10 minutes in the absence of disease progression or unacceptable toxicity.
Fludarabine: Given IV
Cyclophosphamide: Given IV
Total-Body Irradiation: Undergo TBI
Umbilical Cord Blood Transplantation: Undergo UCBT
Dilanubicel: Given IV | 0 |
| Regimen B (Anti-cancer Drugs Plus TBI, Followed by Unmanipulated Cord Blood and Dilanubicel) Patients receive fludarabine IV over 30-60 minutes on days -6 to -2, cyclophosphamide IV on day -6, thiotepa IV over 4 hours on days -5 to -4, and undergo TBI QD on days -2 to -1 (totaling 400 cGy). Patients then undergo umbilical cord blood transplant on day 0. Between 4-24 hours after transplant completion, patients receive dilanubicel IV over 5-10 minutes in the absence of disease progression or unacceptable toxicity.
Fludarabine: Given IV
Cyclophosphamide: Given IV
Thiotepa: Given IV
Total-Body Irradiation: Undergo TBI
Umbilical Cord Blood Transplantation: Undergo UCBT
Dilanubicel: Given IV | 1 |
| Total | 1 |
Baseline characteristics
| Characteristic | Regimen B (Anti-cancer Drugs Plus TBI, Followed by Unmanipulated Cord Blood and Dilanubicel) | Total | Regimen A (Fludarabine, Cyclophosphamide, TBI, Followed by Unmanipulated Cord Blood and Dilanubicel) |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 1 Participants | 0 Participants |
| Age, Continuous | 21 years | 21 years | — |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | — |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 0 Participants | 0 Participants | — |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | — |
| Matched cord blood unit with either homozygous or heterozygous CCR5Δ32 mutation. Heterozygous CCR5Δ32 Mutation in CBU | 0 Participants | 0 Participants | — |
| Matched cord blood unit with either homozygous or heterozygous CCR5Δ32 mutation. Homozygous CCR5Δ32 Mutation in CBU | 1 Participants | 1 Participants | — |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | — |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | — |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | — |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | — |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | — |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | — |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | — |
| Region of Enrollment United States | 1 participants | 1 participants | — |
| Sex: Female, Male Female | 0 Participants | 0 Participants | — |
| Sex: Female, Male Male | 1 Participants | 1 Participants | — |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 0 | 1 / 1 |
| other Total, other adverse events | 0 / 0 | 1 / 1 |
| serious Total, serious adverse events | 0 / 0 | 1 / 1 |
Outcome results
Primary
Primary Graft Failure Rejection
Will be defined by no neutrophil recovery by day 45 (regardless of donor chimerism) or autologous recovery (neutrophil recovery but \< 10% donor chimerism in blood and bone marrow) by day 36. This outcome was originally intended to be assessed for per the aforementioned definitions, but was only able to be assessed through 35 days post-transplant.
Time frame: Up to day 35 post-transplant
Population: No participants were enrolled to Regimen A of the study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Regimen B (Anticancer Drugs, TBI, Dilanubicel) | Primary Graft Failure Rejection | 0 Participants |
Secondary
Change in HIV-1 Induced Inflammatory Immune Responses
HIV viral load by PCR (copies per milliliter; mL)
Time frame: Up to 2 years
Population: No participants survived until 2 years, so outcome could not be measured.
Secondary
HIV Rebound Following Antiretroviral Therapy (ART) Cessation
Count of participants with HIV rebound, measured by HIV viral load by PCR (copies per milliliter; mL)
Time frame: Up to 2 years
Population: No participants survived until 2 years, so outcome could not be measured.
Secondary
Human Immunodeficiency Virus (HIV) Plasma Viral Load
Assess CCR5Δ32 cord blood stem cell engraftment and its effect on biomarkers of HIV-1 infection, including plasma viral load and replication-competent reservoirs, as well as in gut and other sites (if tissue samples are available). This outcome was originally intended to be assessed weekly for up to 2 years post-transplant, but was only able to be assessed through 35 days post-transplant.
Time frame: Baseline and weekly to 35 days post-transplant
Population: No participants were enrolled to Regimen A of the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Regimen B (Anticancer Drugs, TBI, Dilanubicel) | Human Immunodeficiency Virus (HIV) Plasma Viral Load | 0 percentage of viral load change |
Secondary
Immune Homeostasis
Concentration of immunity cells per microliters after transplant
Time frame: Up to 2 years
Population: No participants survived until 2 years, so outcome could not be measured.
Secondary
Immune Reconstitution
Concentration of immunity cells per microliters after transplant
Time frame: Up to 2 years
Population: No participants survived until 2 years, so outcome could not be measured.
Secondary
Incidence of Chronic GVHD
Will be defined by the 2014 NIH criteria. This outcome was originally intended to be assessed for up to 2 years post-transplant, but was only able to be assessed through 35 days post-transplant.
Time frame: 35 days post-transplant
Population: No participants were enrolled to Regimen A of the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Regimen B (Anticancer Drugs, TBI, Dilanubicel) | Incidence of Chronic GVHD | 0 Number of cGVHD Events |
Secondary
Incidence of Infusion Toxicities
Defined as Common Terminology Criteria for Adverse Events version 5.0 grade \>= 3 events.
Time frame: Within the first 24 hours after infusion
Population: No participants were enrolled to Regimen A of the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Regimen B (Anticancer Drugs, TBI, Dilanubicel) | Incidence of Infusion Toxicities | 0 infusion toxicity events |
Secondary
Incidence of Non-relapse Mortality
Will be defined as death without a prior relapse. This outcome was originally intended to be assessed for up to 180 days post-transplant, but was only able to be assessed through 35 days post-transplant.
Time frame: 35 days post-transplant
Population: No participants were enrolled to Regimen A of the study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Regimen B (Anticancer Drugs, TBI, Dilanubicel) | Incidence of Non-relapse Mortality | 1 Participants |
Secondary
Incidence of Severe (Grades III-IV) Acute Graft Versus Host Disease (GVHD)
Will be defined by the 2014 National Institutes of Health (NIH) criteria. This outcome was originally intended to be assessed for up to 2 years post-transplant, but was only able to be assessed through 35 days post-transplant.
Time frame: 35 days post-transplant
Population: No participant was enrolled to Regimen A of the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Regimen B (Anticancer Drugs, TBI, Dilanubicel) | Incidence of Severe (Grades III-IV) Acute Graft Versus Host Disease (GVHD) | 0 Number of Grade 3/4 aGVHD Events |
Secondary
Median Number of Days Post-Transplant to Neutrophil Recovery Occurred
Neutrophil recovery is defined as the first day of 2 consecutive days of absolute neutrophil count \>= 500 after the first post-cord blood transplant nadir. This outcome was originally intended to be assessed for up to 45 days post-transplant, but was only able to be assessed through 35 days post-transplant.
Time frame: Up to Day 35 post-transplant
Population: No participants were enrolled to Regimen A of the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Regimen B (Anticancer Drugs, TBI, Dilanubicel) | Median Number of Days Post-Transplant to Neutrophil Recovery Occurred | 16 Days post-transplant |
Secondary
Platelet Engraftment
Will be defined as the first day of a platelet count \> 20,000/ul with subsequent transfusions for 7 days. This outcome was originally intended to be assessed for up to 2 years post-transplant, but was only able to be assessed through 35 days post-transplant.
Time frame: 35 days post-transplant
Population: No participants were enrolled to Regimen A of the study. The single Regimen B participant did not achieve platelet engraftment prior to death on Day +35 post-transplant.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Regimen B (Anticancer Drugs, TBI, Dilanubicel) | Platelet Engraftment | 0 Participants |
Secondary
Viral Kinetics Following ART Cessation
HIV viral load by PCR (copies per milliliter; mL)
Time frame: Up to 2 years
Population: No participants survived until 2 years, so outcome could not be measured.