Luspatercept for Clonal Cytopenias of Uncertain Significance

Inclusion Criteria

• •Male or female ≥ 18 years of age.
• •Documentation of a CCUS diagnosis.
• •* Clonal cytopenia of undetermined significance (CCUS) is defined as clonal hematopoiesis of indeterminate potential (CHIP) detected in the presence of one or more persistent cytopenias that are otherwise unexplained by hematologic or non-hematologic conditions and that do not meet diagnostic criteria for defined myeloid neoplasms. Cytopenia definitions for diagnosis of CCUS include Hb \<13 g/dL in males and \<12 g/dL in females for anemia, absolute neutrophil count \<1.8 ×109/L for leukopenia, and platelets \<150 × 109/L for thrombocytopenia.
• •* Patients should harbor somatic mutations of myeloid malignancy-associated genes detected in the blood or bone marrow at a variant allele fraction (VAF) of ≥ 2% (≥4% for X-linked gene mutations in males
• •Clinically significant cytopenias demonstrated in two separate lab draws 3 months apart and defined as cytopenia in any one of the following:
• •* Anemia: Transfusion dependent (LTD or HTD for Hb \< 9 g/dL based on IWG 2018 criteria). Exception for higher threshold up to 10g/dL for documented moderate or severe angina pectoris, cardiac or pulmonary insufficiency, or ischemic neurologic diseases (per IWG 2018 consensus recommendation).
• •* Anemia NTD: symptomatic NTD CCUS with Hb \<10 g/dl, symptomatic defined as moderate or worse on ≥ 1 Patient Global Impression of Severity (PGI-S) item (fatigue, shortness of breath, weakness, or dizziness)
• •* Thrombocytopenia: platelet count less than 30,000 /microL or \< 50,000/microL with documented bleeding events or high risk for bleeding, for example on blood thinners or drugs that inhibit platelet function for other comorbidities.
• •* Neutropenia: Neutropenia below 750/microl are included in the study. For subjects with neutropenia between 750-1000/microl, subjects should have neutropenia AND a history of serious infection(s).
• •Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2
• •Adequate organ function as defined by:
• •* Direct bilirubin \< 3 x ULN. Indirect hyperbilirubinemia from hemolysis or Gilberts disease are not considered as impaired.
• •* Estimated Creatinine clearance \>30 ml/min by institutional standard (either MDRD or Cockcroft Gault or measured by 24 hour urine clearance.
• •* ALT and AST \< 3 x ULN
• •Females of childbearing potential (FCBP), defined as a sexually mature woman who: 1) has achieved menarche at some point, 2) not undergone a hysterectomy or bilateral oophorectomy or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy or amenorrhea due to other medical reasons does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months), must:
• •* Have two negative pregnancy tests (serum or urine) as verified by the investigator prior to starting study therapy (unless the screening pregnancy test was done within 72 hours of W1D1). She must agree to ongoing pregnancy testing during the course of the study, and after end of study treatment.
• •* Either commit to true abstinence1 from heterosexual contact (which must be reviewed on a monthly basis and source documented) or agree to use, and be able to comply with, highly effective contraception2 without interruption, 5 weeks prior to starting investigational product, during the study therapy (including dose interruptions), and for 12 weeks after discontinuation of study therapy.
• •Male subjects must:
• •\- Practice true abstinence1(which must be reviewed prior to each IP administration or on a monthly basis \[e.g., in the event of dose delays\]) or agree to use a condom (latex or non-latex, but not made out of natural \[animal\] membrane) during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for at least 12 weeks following investigational product discontinuation, even if he has undergone a successful vasectomy.
• •Contraception
• •True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. \[Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception\].
• •Highly effective contraception is defined in this protocol as the following (information will also appear in the ICF): Hormonal contraception (for example, birth control pills, injection, implant, transdermal patch, vaginal ring); intrauterine device (IUD); tubal ligation (tying your tubes); or a partner with a successful vasectomy.