Background: Immune bone marrow failure is a condition that occurs when a person s immune system attacks the cells of the bone marrow. This can lead to diseases including different types of anemias and blood cancers. Some of these diseases can be deadly. Better treatments are needed. Objective: To test a drug (ruxolitinib) in people with different types of immune bone marrow failure. Eligibility: Adults aged 18 and older with an immune bone marrow failure. Design: Participants will be screened. They will have a physical exam. They will give samples of blood and saliva. They will have a bone marrow biopsy: A large needle will be inserted into a small cut to remove a sample of the soft tissue inside the bone. Some participants may have a skin biopsy: A small piece of skin will be removed. Some may have a computed tomography (CT) scan: They will lie on a table that slides into a donut-shaped machine that uses X-rays to make pictures of the inside of the body. Ruxolitinib is a tablet taken by mouth. Participants will take the drug twice a day for up to 6 months. Participants will have blood tests every week while they are taking the drug. These tests can be done by the participant s own physician and the results sent to the researchers. Participants will have clinic visits after taking the drug for 3 months and 6 months and then after 1, 2, and 3 years. The blood tests and bone marrow biopsy will be repeated. Participants who improve while taking the drugs may go on to an extension phase of the study.
Study Description: This is a prospective, non-randomized, phase I/II study in which participants with relapsed/refractory immune marrow failure (severe aplastic anemia, moderate aplastic anemia, single lineage cytopenias, T-LGL, and hypoplastic MDS) will be treated with the JAK1/2 inhibitor ruxolitinib. Our hypothesis is that JAK1/2 inhibition with ruxolitinib will result in hematologic improvement in participants with immune marrow failure. Objectives: The primary objectives are to assess safety and efficacy of the JAK1/2 inhibitor ruxolitinib in immune marrow failure. The secondary objectives are to assess early and long-term hematologic response, depth of response, development of transfusion independence, rate of relapse, rate of clonal evolution to myeloid malignancy and Paroxysmal Nocturnal Hemoglobinuria (PNH), 3-year overall survival, response after re-initiation of therapy in relapsed participants, maximum tolerated dose. Endpoints: The primary endpoints are: (a) the primary safety endpoint will be number of participants who complete a full course of ruxolitinib without cessation required by hematologic toxicity in the 6 months following treatment initiation; (b) The primary efficacy endpoint is overall response (OR) rate by 6 months. The secondary endpoints are time to OR, OR at 3 months, development of transfusion independence at 3 and 6 months, type of response at 3 and 6 months, rate of relapse up to 3 years, rate of clonal evolution up to 3 years, 3-year overall survival (OS), and number of participants tolerating maximum ruxolitinib dose.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
13
Participants will be instructed to take ruxolitinib at up to 20mg (total) BID for up to 6 months (with or without food). The dose will be increased weekly in 5 mg twice-daily increments, up to a maximum dose of 20 mg by mouth twice daily.
National Institutes of Health Clinical Center
Bethesda, Maryland, United States
Number of Participants Who Completed a Full Course of Ruxolitinib Without Discontinuation Due to Hematologic Toxicity
Numbers of participants who complete a full course of ruxolitinib without discontinuation due to hematologic toxicity in the 6 months following treatment initiation. Discontinuation due to hematologic toxicity is defined as those participants that remain off drug for 6 consecutive weeks due to ongoing hematologic toxicity. Hematologic toxicity for this study will be defined as follows: * Greater than 50% increase in transfusion needs in participants who were transfusion dependent prior to ruxolitinib therapy, lasting for more than 12 weeks * Need for any transfusion for more than 12 weeks in participants who were transfusion independent prior to ruxolitinib therapy. This excludes transfusions given for Hb \>7g/dL or platelets \>10 x 109 or those given for procedures. * Worsening in peripheral cytopenias \>50% compared to pre-treatment levels in participants with a pre-treatment ANC \>500 or platelets \>50 Drop in ANC to \<200 in participants with a pre-treatment ANC \<500
Time frame: 6 months
Number of Participants Who Achieved an Overall Response
Participants who had a CR at 3 months and discontinued study drug were considered responders, even if they subsequently relapsed. • Cohort 1: Response: No Camitta SAA criteria; ≥2 of ANC ≥0.5 × 10⁹/L, platelets ≥20 × 10⁹/L, reticulocytes ≥60 × 10⁹/L on 2 counts ≥1 week apart Complete Response (CR): ANC ≥1 × 10⁹/L, platelets ≥100 × 10⁹/L, Hb ≥10 g/dL Partial Response (PR): Response but not CR • Cohorts 3: Response: ≥1 evaluable lineage response Erythroid: Hb ↑ \>1.5 g/dL, ≥4 fewer RBC transfusions/8 weeks, or reticulocytes \>60 × 10⁹/L Platelet: ↑ ≥30 × 10⁹/L if baseline ≥20 × 10⁹/L, or \<20 to \>20 × 10⁹/L and ≥100% ↑ Neutrophil: ≥100% ↑ and absolute ↑ \>0.5 × 10⁹/L CR: ANC ≥1 × 10⁹/L, platelets ≥100 × 10⁹/L, Hb ≥10 g/dL • Cohort 4: Response: ≥1 evaluable lineage response CHR: ANC \>1.5 × 10⁹/L, platelets \>150 × 10⁹/L, lymphocytes \<4 × 10⁹/L PHR: Improvement in ≥1 affected parameter but not CHR CMR: No clonal T-cell detection and CHR CR: CHR and CMR
Time frame: 6 months
Hematological Response
Time frame: 3, 12 months, and yearly thereafter
Depth of Response
Time frame: 3, 6 months
Rate of Clonal Evolution
Time frame: Variable
Rate of Relapse
Time frame: Variable
Time to Transfusion Independence
Time frame: Variable
Overall Survival
Time frame: Variable
Hematological Response of Relapse Subjects That Re-start Treatment
Time frame: Variable
Percent of Patients Tolerating 20 mg Ruxolitinib BID.
Time frame: Variable
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