Aplastic Anemia
Conditions
Brief summary
This phase II trial tests how well a ruxolitinib-based graft versus host disease (GVHD) prevention (prophylaxis) regimen works before, during, and after bone marrow/stem cell transplantation (hematopoietic cell transplantation \[HCT\]) in patients with acquired aplastic anemia. Acquired aplastic anemia (AA) is a condition in which the bone marrow is unable to produce blood cells. Affected patients typically present with infections due to abnormally low number of neutrophils, bleeding due to low platelet count, and/or fatigue due to a lower-than-normal number of red blood cells (anemia). Its incidence varies with age, occurring most frequently in patients aged 2-5 years, 20-25 years, and 55 years and older. Treatment of AA includes either immunosuppressive therapy (IST) or bone marrow/stem cell transplantation (HCT) with first-line therapy in younger adults often being HCT, while adults over 40 still frequently trial IST first due to the morbidity and mortality concerns with HCT. GVHD is a common complication after donor stem cell transplantation, resulting from donor immune cells recognizing recipients' cells and attacking them. Ruxolitinib, a drug in a class of oral medications called JAK inhibitors has been approved for the treatment of acute and chronic GVHD. It has also been shown to decrease GVHD when used in the prevention setting in patients with myelofibrosis. The current study aims to assess whether adding ruxolitinib to a standard GVHD prevention regimen may reduce the risk of Grade II-IV acute and chronic GVHD after bone marrow/stem cell transplantation in older patients with acquired aplastic anemia.
Detailed description
OUTLINE: CONDITIONING REGIMEN: Patients receive fludarabine intravenously (IV) over 30 minutes once daily (QD) on days -4, -3, and -2 and undergo total body irradiation (TBI) in one or two fractions on day -1. TRANSPLANT: Patients undergo peripheral blood stem cell (PBSC) or bone marrow transplant on day 0. GVHD PROPHYLAXIS: Cyclosporine, Sirolimus, mycophenolate mofetil (MMF), Ruxolitinib HUMAN LEUKOCYTE ANTIGEN (HLA)-MATCHED: Patients receive cyclosporine orally (PO) every 12 hours (Q12H) on days -3 to 96 with taper beginning on day 97 until day 180 (until day 150 for patients with unrelated donors), ruxolitinib PO twice daily (BID) or QD on day -5 to 365 and mycophenolate mofetil (MMF) PO 4-6 hours after transplant and then every 8 hours (Q8H) until day 29, then reduced to Q12H on days 30-40. Patients with unrelated donors also receive sirolimus PO QD on days -3 to 150 with taper beginning on day 151 until day 180. Patients also begin granulocyte colony-stimulating factor (G-CSF) subcutaneously (SC) on day 1 to continue until absolute neutrophil count (ANC) \> 1000/mm\^3 x 3 days. Patients also undergo multi-gated acquisition scan (MUGA)/echocardiogram (ECHO) and computed tomography (CT) during screening, as well as collection of blood samples and bone marrow aspiration and biopsy throughout the study. HLA-MISMATCHED: Patients receive cyclosporine PO Q12 on days -3 to 150 with taper beginning on day 151 until day 180, sirolimus PO QD on days -3 to 180 with taper beginning on day 181 until day 365, ruxolitinib PO BID or QD on day -5 to 365, and MMF PO 4-6 hours after transplant and then Q8 until day 29, then reduced to Q12H on days 30-40. Patients also begin G-CSF SC on day 1 to continue until ANC \> 1000/mm\^3 x 3 days. Patients also undergo MUGA/ECHO and CT during screening, as well as collection of blood samples and bone marrow aspiration and biopsy throughout the study.
Interventions
PROCEDUREBiospecimen Collection
Undergo blood sample collection
PROCEDUREBone Marrow Aspiration
Undergo bone marrow biopsy and aspiration
PROCEDUREBone Marrow Biopsy
Undergo bone marrow biopsy and aspiration
PROCEDUREBone Marrow Transplantation
Undergo bone marrow transplant
PROCEDUREComputed Tomography
Undergo CT
DRUGCyclosporine
Given PO
DRUGFludarabine
Given IV
DRUGGranulocyte Colony-Stimulating Factor
Given SC
DRUGMycophenolate Mofetil
Given PO
PROCEDUREPeripheral Blood Stem Cell Transplantation
Undergo PBSC transplantation
DRUGRuxolitinib
Given PO
DRUGSirolimus
Given PO
RADIATIONTotal-Body Irradiation
Undergo TBI
PROCEDUREMultigated Acquisition Scan
Undergo MUGA
PROCEDUREEchocardiography
Undergo ECHO
Sponsors
Fred Hutchinson Cancer Center
Incyte Corporation
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age \> 40 years or ages 18 - 40 years with Hematopoietic Cell Transplantation - Specific Comorbidity Index (HCT-CI) score \> 3 necessitating a low intensity transplant or determined inability to tolerate antithymocyte globulin (ATG) * Diagnosis of severe acquired aplastic anemia defined as a bone marrow hypoplasia (\< 25% or 25-50% with \< 30% residual hematopoietic cells) shown by a biopsy and at least two of the three following criteria: absolute neutrophil count (ANC) \< 0.5×10\^9/L, platelets \< 20×10\^9/L, or absolute reticulocytes \< 40×10\^9/L or * Non-severe acquired aplastic anemia defined as a hypocellular marrow and transfusion dependent (red cells and/or platelets) * Does not meet World Health Organization (WHO) criteria for myelodysplastic syndrome (MDS) * Ability to understand and the willingness to sign a written informed consent document * Patient must be a potential hematopoietic stem cell transplant candidate as assessed by the consenting physician * Karnofsky ≥ 70 * Calculated creatinine clearance using the Cockcroft-Gault formula or 24 hr urine creatinine clearance must be \> 60 ml/min * Total serum bilirubin must be \< 2 mg/dL unless the elevation is thought to be due to Gilbert's disease or hemolysis * Transaminases must be \< 3x the upper limit of normal * Patients with clinical or laboratory evidence of liver disease will be evaluated for the cause of liver disease, its clinical severity in terms of liver function, and the degree of portal hypertension. Patients with fulminant liver failure, cirrhosis with evidence of portal hypertension or bridging fibrosis, alcoholic hepatitis, hepatic encephalopathy, or correctable hepatic synthetic dysfunction evidenced by prolongation of the prothrombin time, ascites related to portal hypertension, bacterial or fungal abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin \> 3mg/dL, and symptomatic biliary disease will be excluded * Diffusing capacity for carbon monoxide (DLCO) corrected \> 60% normal * May not be on supplemental oxygen * Left ventricular ejection fraction \> 40% OR shortening fraction \> 26% * Patients may have received prior treatment for their AA but they are NOT required to have received immune suppression prior to consideration for transplant
Exclusion criteria
* Contraindication to receiving ruxolitinib including: patients who have known hypersensitivity to JAK inhibitors and excipients * Patients with history of myocardial infarction (MI), cerebrovascular accident (CVA) or unprovoked pulmonary embolism (PE)/deep vein thrombosis (DVT) in past 6 months * History of prior allogeneic transplant * Active or recent infection without infectious disease (ID) consult and approval * History of untreated tuberculosis (TB) * History of HIV infection * Pregnant or breastfeeding * History of prior malignancy with \> 20% risk of recurrence in the next 5 years * Patients without an HLA-identical sibling donor, 10 of 10 HLA-matched or 9 of 10 mismatched unrelated donor that meet transplant criteria
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of grades II-IV acute graft-versus-host disease (GVHD) | At day 100 | Will be estimated as simple proportions and informally compared to the historical controls at Fred Hutch. (i.e., estimates presented descriptively, but no formal statistical comparisons will be made). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of grade III-IV acute GVHD | At day 100 | Will be estimated as simple proportions and informally compared to the historical controls at Fred Hutch. (i.e., estimates presented descriptively, but no formal statistical comparisons will be made). |
| Incidence of chronic GVHD | At 1 year | Will be estimated as simple proportions and informally compared to the historical controls at Fred Hutch. (i.e., estimates presented descriptively, but no formal statistical comparisons will be made). |
| Incidence of primary graft failure | At 2 years | Will be defined as absence of 3 consecutive days with neutrophils ≥ 500/ul combined with host CD3 peripheral blood chimerism ≥ 50% at day 42; absence of 3 consecutive days with neutrophils ≥ 500/ul under any circumstances at day 55; death after day 28 with neutrophil count \<100/ul without any evidence of engraftment (\< 5% donor CD3) and; primary autologous count recovery with \< 5% donor CD3 peripheral blood chimerism at count recovery and without relapse. |
| Nonrelapse mortality | At day 100 | Kaplan-Meier curve will be generated with point estimates and 95% confidence intervals, and Log-rank test will be conducted. |
| Overall survival | At 1 year | Kaplan-Meier curve will be generated with point estimates and 95% confidence intervals, and Log-rank test will be conducted. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORRachel B. Salit, MD
Fred Hutch/University of Washington Cancer Consortium
Outcome results
None listed