Calcineurin Inhibitor-Free GVHD Prevention Regimen After Related Haplo PBSCT

Study Overview
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Brief Summary
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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.

Official Title
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A Calcineurin Inhibitor-Free GVHD Prevention Regimen After Related Haploidentical Peripheral Blood Stem Cell Transplantation

Conditions
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Non-Hodgkin's Lymphoma, Acute Leukemia in Remission, Chronic Myeloid Leukemia, Primary Myelofibrosis, Chronic Myelomonocytic Leukemia, Myelodysplastic Syndromes, Hodgkin Lymphoma, Multiple Myeloma

Intervention / Treatment
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* Drug: Fludarabine
* Drug: Busulfan
* Drug: Cyclophosphamide
* Radiation: Total body irradiation (TBI)
* Procedure: Peripheral Blood Hematopoietic Cell Transplantation (HCT)
* Drug: Sirolimus (SIR)
* Drug: Mycophenolate mofetil (MMF)
* Drug: Granulocyte-colony stimulating factor (G-CSF)


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Conditioning/HCT/GVHD Prophylaxis<br>Pre-HCT Conditioning, HCT, GVHD Prophylaxis. Conditioning regimen: To reduce heterogeneity, two commonly used myeloablative (MAC) and reduced intensity (RIC) regimens are permitted on this trial. Myeloablative conditioning: fludarabine, busulfan. Reduced intensity conditioning: fludarabine, cyclophosphamide, total body irradiation. Peripheral blood hematopoietic cell transplantation Graft vs. Host Disease (GVHD) prevention treatment: cyclophosphamide, mycophenolate mofetil, sirolimus. Growth factor support: G-CSF | Drug: Fludarabine<br>* 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.<br>* Other names: Fludara, Oforta;Drug: Busulfan<br>* 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).<br>* Other names: Busulfex, Myleran;Drug: Cyclophosphamide<br>* 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.<br>* Other names: Cytoxan;Radiation: Total body irradiation (TBI)<br>* Reduced intensity conditioning: 200 centigray (cGy) on day -1.<br>* Other names: radiotherapy;Procedure: Peripheral Blood Hematopoietic Cell Transplantation (HCT)<br>* On day 0, patients will receive a peripheral blood hematopoietic cell graft.<br>* Other names: cell graft;Drug: Sirolimus (SIR)<br>* 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.<br>* Other names: Rapamune;Drug: Mycophenolate mofetil (MMF)<br>* 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.<br>* Other names: CellCept;Drug: Granulocyte-colony stimulating factor (G-CSF)<br>* 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.<br>* Other names: Neupogen, Filgrastim;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 100 days post hematopoietic cell transplant (HCT) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Chronic GVHD | Cumulative incidence of chronic GVHD by 1 year. Chronic GVHD diagnosis follow National Institutes of Health (NIH) Consensus guidelines. | 1 year post HCT | 
| 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. | Up to 1 year post HCT | 
| 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. | Up to 1 year post HCT | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute leukemia in CR, Chronic myeloid leukemia, Non-Hodgkin lymphoma in high risk, Graft vs. Host Disease, GVHD, Hematopoietic cell transplant (HCT)