This pilot phase I trial studies the side effects of combination chemotherapy, total body irradiation, and donor blood stem cell transplant in treating patients with secondary myelofibrosis. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy x-rays to kill cancer cells and shrink tumors. Giving combination chemotherapy and total body irradiation before a donor blood stem cell transplant helps to stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets.
PRIMARY OBJECTIVE: I. To evaluate the safety and tolerability of reduced-intensity (fludarabine/melphalan) haploidentical hematopoietic cell transplantation (Haplo-HCT) followed by post-transplant cyclophosphamide (PTCy) in patients with advanced myelofibrosis (MF), as assessed by the evaluation of toxicities, including type, frequency, severity, attribution, time course and duration. SECONDARY OBJECTIVES: I. To summarize and evaluate hematologic (neutrophil and platelet) recovery. II. To evaluate and describe cytokine release syndrome (CRS) post haploidentical HCT in the setting of advanced myelofibrosis, as assessed by grade, frequency, severity, duration and reversibility (outcome). III. To estimate graft failure-free survival (GFS) at 100-days post-transplant. IV. To estimate overall survival (OS), progression-free survival (PFS) and cumulative incidence (CI) of relapse/progression, and non-relapse mortality (NRM) at 100-days, 1-year, and 2-year post transplant. V. To estimate the cumulative incidence of acute graft-versus-host disease (GvHD), grade II-IV, at 100-days post-transplant (per Keystone Consensus modification of the Glucksberg criteria). VI. To estimate the cumulative incidence of chronic GvHD at 1-year and 2-year post transplant (per National Institutes of Health \[NIH\] Consensus Criteria). VII. To characterize the severity and extent of acute and chronic GvHD. EXPLORATORY OBJECTIVE: I. To conduct correlative studies and describe inflammatory cytokine levels and GVHD biomarker levels in plasma and T cell differentiation/functions in patients enrolled onto the trial. OUTLINE: Patients receive melphalan intravenously (IV) over 30 minutes on day -5, fludarabine IV over 30-60 minutes on days -5 to -2. Patients undergo total body irradiation (TBI) on day -1 and hematopoietic cell transplantation (HCT) on day 0. Patients receive cyclophosphamide IV over 1-2 hours on days 3 and 4. Starting on day 5, patients receive tacrolimus IV then orally (PO) for 6 months followed by a taper, mycophenolate mofetil PO thrice daily (TID) until day 35, and glycosylated recombinant human G-CSF AVI-014 (G-CSF) IV daily until absolute neutrophil count \> 1,500/mm\^3 for 3 consecutive days. Treatment continues in the absence of disease progression or unexpected toxicity. After completion of study treatment, patients are followed for up to 2 years.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
22
Undergo HCT
Given IV
Given IV
Given IV
Correlative studies
Given IV
Given PO
Given IV or PO
Undergo TBI
City of Hope Medical Center
Duarte, California, United States
Incidence of adverse events
Assessed by Bearman Toxicity Scale and National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version (CTCAE) 4.03. Observed toxicities will be summarized in terms of type (organ affected or laboratory determination), severity, time of onset, duration, probable association with the study regimen and reversibility or outcome.
Time frame: Up to 100 days post-hematopoietic cell transplantation (HCT)
Incidence of unacceptable toxicity
Assessed by Bearman Toxicity Scale and NCI CTCAE version 4.03. Observed toxicities will be summarized in terms of type (organ affected or laboratory determination), severity, time of onset, duration, probable association with the study regimen and reversibility or outcome.
Time frame: Up to 2 years
Neutrophil recovery
Defined as the first of 3 measurements on different days when the patient has an absolute neutrophil count of \>= 500/uL after conditioning.
Time frame: Up to 2 years
Platelet recovery
Defined as the first day of a minimum of 3 measurements on different days that the patient has achieved a platelet count \>= 20,000/uL and did not receive a platelet transfusion in the previous 7 days.
Time frame: Up to 2 years
Incidence of cytokine release syndrome (CRS)
Defined and graded per American Society for Transplantation and Cellular Therapy (ASTCT) criteria.
Time frame: After haploidentical HCT, assessed up to 2 years
Graft failure-free survival
Will be calculated using Kaplan-Meier product-limit method, 95% confidence intervals will be calculated.
Time frame: Time from start of protocol treatment/infusion of stem cell product to graft-failure, death (from any cause), or last contact, whichever occurs first, assessed up to 2 years
Overall survival
Will be calculated using Kaplan-Meier product-limit method, 95% confidence intervals will be calculated.
Time frame: Time from start of protocol treatment/infusion of stem cell product to death (from any cause), or last contact, whichever occurs first, assessed up to 36 months
Progression-free survival
Will be calculated using Kaplan-Meier product-limit method, 95% confidence intervals will be calculated.
Time frame: Time from start of protocol treatment/infusion of stem cell product to, relapse, progression, death (from any cause), or last contact, whichever occurs first, assessed up to 2 years
Cumulative incidence of relapse/progression
The cumulative incidence of relapse/progression will be estimated using the method described by Gooley et al. (1999).
Time frame: Up to 2 years
Non-relapse mortality (NRM)
The cumulative incidence of NRM will be estimated using the method described by Gooley et al. (1999).
Time frame: Up to 2 years
Cumulative incidence of acute graft versus host disease (GvHD)
Assessed by Keystone Consensus criteria. Time to the first day of acute GvHD onset (of any grade) will be used to estimate the cumulative incidence.
Time frame: Up to day 100 post-HCT
Cumulative incidence of chronic graft versus host disease GvHD
Assessed by National Institutes of Health Consensus Criteria. Time to the first day of chronic GvHD onset (of any grade) will be used to estimate the cumulative incidence.
Time frame: Up to 2 years post-HCT
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