Non-Hodgkin's Lymphoma, Acute Leukemia in Remission, Chronic Myeloid Leukemia, Primary Myelofibrosis, Chronic Myelomonocytic Leukemia, Myelodysplastic Syndromes, Hodgkin Lymphoma, Multiple Myeloma
Conditions
Keywords
Acute leukemia in CR, Chronic myeloid leukemia, Non-Hodgkin lymphoma in high risk, Graft vs. Host Disease, GVHD, Hematopoietic cell transplant (HCT)
Brief summary
The purpose of this study is to find out if a combination of drugs (these are called: cyclophosphamide, sirolimus, and mycophenolate mofetil) will protect participants better against graft vs. host disease (GVHD) after receiving a hematopoietic cell transplant from a related partially matched (haploidentical) donor. As part of the treatment for their blood cancer, participants need a hematopoietic cell transplantation (HCT) to improve their chances of cure. In any HCT, after the stem cell infusion is given, a combination of drugs is needed to prevent GVHD and facilitate acceptance of the graft.
Interventions
DRUGFludarabine
Myeloablative conditioning: 40 mg/m\^2 daily for 4 days. Dose will be adjusted for estimated creatinine clearance. Reduced intensity conditioning: 30 mg/m\^2 daily on days -6, -5, -4, -3 and -2. Dose will be adjusted for estimated creatinine clearance.
DRUGBusulfan
Myeloablative conditioning: IV dosing targeted for a daily total area under curve (AUC) 5300 mmol\*min/L for 4 days. Busulfan AUC will be pharmacokinetically targeted. An AUC 3500 mmol\*min/l may be considered in patients over 60 years of age or with multiple comorbidities. Chemotherapy may start on day -6 or day -5 depending on the day of admission (-6 for Wednesday admission, -5 for Sunday admission).
DRUGCyclophosphamide
Reduced intensity conditioning: 14.5 mg/kg/day on days -6, -5. GVHD prophylaxis: 50 mg/kg ideal body weight (IBW) daily dose will be given on days +3 and +4 post-transplant as an IV infusion over 1-2 hours.
RADIATIONTotal body irradiation (TBI)
Reduced intensity conditioning: 200 centigray (cGy) on day -1.
PROCEDUREPeripheral Blood Hematopoietic Cell Transplantation (HCT)
On day 0, patients will receive a peripheral blood hematopoietic cell graft.
DRUGSirolimus (SIR)
GVHD prophylaxis: SIR will be administered as a 9 mg oral loading dose on day +5, followed by maintenance. SIR levels will be monitored and maintenance dosing adjusted as needed for a target trough level 8 to 14 ng/ml, per Moffitt BMT program standard practice. In the absence of acute GVHD, sirolimus taper will start on day +90 (+/- 10 days) and it is suggested to finish by day +180.
DRUGMycophenolate mofetil (MMF)
GVHD prophylaxis: MMF will start on day +5 at a dose of 15 mg/kg every 8 hours IV with the maximum daily dose not to exceed 3 gm. MMF will be changed to orally (PO) and discontinued on day +35 (without taper) in the absence of acute GVHD.
Growth factor support: G-CSF will be given beginning on day 5 at a dose of 5 mcg/kg/day (rounding to the nearest vial dose), until absolute granulocyte count (ANC) is \> 1,000/mm\^3 for three consecutive days. G-CSF may be given IV or subcutaneously.
Sponsors
H. Lee Moffitt Cancer Center and Research Institute
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
Patient Participants: * Age: Must be older than 18 years, no upper age limit. * Karnofsky performance status: Full intensity conditioning, 80-100%; reduced intensity conditioning, 60-100%. * Vital organ function: a) Cardiac: Left ventricular ejection fraction must be \> 45% assessed by multigated acquisition (MUGA) scan or echocardiogram. No myocardial infarction within 6 months of transplant evaluation. b) Pulmonary: forced expiratory volume at one second (FEV1), forced vital capacity (FVC), and adjusted diffusing capacity of the lungs for carbon monoxide (DLCO) must be ≥ 50% of predicted values. c) Liver: Transaminases (AST, ALT) less than 2 times upper limit of normal values. d) Kidney: Estimated creatinine clearance ≥ 50 cc/min. * Signed informed consent. * Included disease conditions and remission status: a) Acute leukemia in First Complete Remission (CR1) or second/subsequent CR. b) Chronic myeloid leukemia, primary myelofibrosis, chronic myelomonocytic leukemia. c) Int-2 or high risk myelodysplastic syndrome (MDS). d) Hodgkin lymphoma beyond CR1 with chemosensitive disease, Stable Disease (SD) may be included if no mass \>3 cm. e) Non-Hodgkin lymphoma in high risk CR1 or subsequent CR (by clinical, cytogenetic or molecular criteria), primary induction failure (PIF) or relapsed with chemosensitive disease. SD may be included if no mass \>3 cm. f) Multiple myeloma in CR/Very Good Partial Response (VGPR). Donor Participants: * Per Moffitt Cancer Center (MCC) Blood and Marrow Transplant (BMT) program practices, an allele level matched (8/8 HLA A, B, C and DR) sibling or unrelated donor is preferred. If a matched donor is not found, mismatched unrelated or haploidentical donors may be considered. * If a haploidentical donor is considered, parents, children, full siblings and in selected cases, extended family, will have high resolution typing at the MCC HLA laboratory. A familiar haploidentical donor is chosen among those who share at least one HLA-A, B, C, DRB1 and DQB1 haplotype with the patient. * Patient will be screened for antibodies targeting mismatched HLA antigens in potential haploidentical donors (donor specific antibodies, DSA). Antibody screen and confirmatory testing using Luminex single antigen-bead test will be done. * Among several potential donors, will choose in order of priority: a) Matched cytomegalovirus (CMV) immunoglobulin G (IgG) serologic status between donor and recipient. b) ABO blood group system-matched donor preferred, then minor ABO mismatch, then major ABO mismatch. c) Younger donor preferred: child, then sibling, and then parent. d) For male recipient, male donor will be preferred. Avoid mother as a donor unless no other choices.
Exclusion criteria
Patient Participants: * Uncontrolled active bacterial, viral, fungal infection. * Prior allogeneic HCT. * Unwilling to comply with study requirements. * Active, progressive or advanced disease based on diagnosis.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Grade II-IV Acute Graft vs. Host Disease (GVHD) | 100 days post hematopoietic cell transplant (HCT) | Cumulative incidence of grade II-IV acute GVHD by day 100 after HCT. Acute GVHD organ staging and assessment of overall grade will use standard consensus criteria. The cumulative incidence of acute and chronic GVHD will be estimated, considering malignancy relapse and non-relapse death as competing risk events. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Chronic GVHD | 1 year post HCT | Cumulative incidence of chronic GVHD by 1 year. Chronic GVHD diagnosis follow National Institutes of Health (NIH) Consensus guidelines. |
| Overall Survival (OS) | Up to 1 year post HCT | Overall survival is defined as time from transplant to death or last follow-up, and is reported as percentage of surviving participants. |
| Progression Free Survival (PFS) | Up to 1 year post HCT | Progression-free survival defined by the time interval from transplant to relapse/recurrence, to death or to last follow-up. Reported as percentage of participants who are disease free one year post HCT. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Conditioning/HCT/GVHD Prophylaxis Pre-HCT Conditioning, HCT, GVHD Prophylaxis. | 32 |
| Total | 32 |
Baseline characteristics
| Characteristic | Conditioning/HCT/GVHD Prophylaxis |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 5 Participants |
| Age, Categorical Between 18 and 65 years | 27 Participants |
| Age, Continuous | 49.5 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 28 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants |
| Race (NIH/OMB) Black or African American | 7 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 | 22 Participants |
| Region of Enrollment United States | 32 participants |
| Sex: Female, Male Female | 12 Participants |
| Sex: Female, Male Male | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 5 / 32 |
| other Total, other adverse events | 5 / 32 |
| serious Total, serious adverse events | 17 / 32 |
Outcome results
Primary
Incidence of Grade II-IV Acute Graft vs. Host Disease (GVHD)
Cumulative incidence of grade II-IV acute GVHD by day 100 after HCT. Acute GVHD organ staging and assessment of overall grade will use standard consensus criteria. The cumulative incidence of acute and chronic GVHD will be estimated, considering malignancy relapse and non-relapse death as competing risk events.
Time frame: 100 days post hematopoietic cell transplant (HCT)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Conditioning/HCT/GVHD Prophylaxis | Incidence of Grade II-IV Acute Graft vs. Host Disease (GVHD) | 18.8 percentage of participants |
Secondary
Incidence of Chronic GVHD
Cumulative incidence of chronic GVHD by 1 year. Chronic GVHD diagnosis follow National Institutes of Health (NIH) Consensus guidelines.
Time frame: 1 year post HCT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Conditioning/HCT/GVHD Prophylaxis | Incidence of Chronic GVHD | 20.0 percentage of participants |
Secondary
Overall Survival (OS)
Overall survival is defined as time from transplant to death or last follow-up, and is reported as percentage of surviving participants.
Time frame: Up to 1 year post HCT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Conditioning/HCT/GVHD Prophylaxis | Overall Survival (OS) | 70.2 percentage of participants |
Secondary
Progression Free Survival (PFS)
Progression-free survival defined by the time interval from transplant to relapse/recurrence, to death or to last follow-up. Reported as percentage of participants who are disease free one year post HCT.
Time frame: Up to 1 year post HCT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Conditioning/HCT/GVHD Prophylaxis | Progression Free Survival (PFS) | 56.6 percentage of participants |