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 clonalhematopoiesis of indeterminate potential (CHIP) detected in the presence of oneor more persistent cytopenias that are otherwise unexplained by hematologic ornon-hematologic conditions and that do not meet diagnostic criteria for definedmyeloid neoplasms. Cytopenia definitions for diagnosis of CCUS include Hb <13g/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 genesdetected 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 monthsapart and defined as cytopenia in any one of the following:

• Anemia: Transfusion dependent (LTD or HTD for Hb < 9 g/dL based on IWG 2018criteria). Exception for higher threshold up to 10g/dL for documented moderateor severe angina pectoris, cardiac or pulmonary insufficiency, or ischemicneurologic diseases (per IWG 2018 consensus recommendation).

• Anemia NTD: symptomatic NTD CCUS with Hb <10 g/dl, symptomatic defined asmoderate 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/microLwith documented bleeding events or high risk for bleeding, for example on bloodthinners or drugs that inhibit platelet function for other comorbidities.

• Neutropenia: Neutropenia below 750/microl are included in the study. Forsubjects with neutropenia between 750-1000/microl, subjects should haveneutropenia 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 orGilberts disease are not considered as impaired.

• Estimated Creatinine clearance >30 ml/min by institutional standard (eitherMDRD 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 bilateraloophorectomy or 3) has not been naturally postmenopausal (amenorrhea followingcancer therapy or amenorrhea due to other medical reasons does not rule outchildbearing potential) for at least 24 consecutive months (i.e., has had menses atany time in the preceding 24 consecutive months), must:

• Have two negative pregnancy tests (serum or urine) as verified by theinvestigator prior to starting study therapy (unless the screening pregnancytest was done within 72 hours of W1D1). She must agree to ongoing pregnancytesting during the course of the study, and after end of study treatment.

• Either commit to true abstinence1 from heterosexual contact (which must bereviewed on a monthly basis and source documented) or agree to use, and be ableto comply with, highly effective contraception2 without interruption, 5 weeksprior to starting investigational product, during the study therapy (includingdose 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 oron 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 sexualcontact with a pregnant female or a female of childbearing potential whileparticipating in the study, during dose interruptions and for at least 12 weeksfollowing investigational product discontinuation, even if he has undergone asuccessful vasectomy.

Contraception

• True abstinence is acceptable when this is in line with the preferred and usuallifestyle of the subject. [Periodic abstinence (e.g., calendar, ovulation,symptothermal, post-ovulation methods) and withdrawal are not acceptable methods ofcontraception].

• 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 asuccessful vasectomy.

Exclusion Criteria:

• Concurrent malignancy requiring active systemic therapy

• Diagnosis of MDS, AML, MPN or any other myeloid malignancy in the patient's lifetime

• Active uncontrolled infection that in the investigators opinion will affect studyprocedures and/or results

• Active uncontrolled hypertension not responding to blood pressure loweringmedications which in the investigator's opinion will be harmful for the patient.

• Use of ESA or growth factors within four weeks prior to the start of the study

• Known risk factors for thromboembolism (splenectomy, concomitant use of hormonereplacement therapy or recent uncontrolled pulmonary embolism or DVT in the last 6months). Subjects adequately controlled on anticoagulation are permitted.

• Pregnant or nursing women, where pregnancy is defined as the state of a female afterconception and until the termination of gestation, confirmed by a positive hCGlaboratory test. Women of child-bearing potential, defined as all womenphysiologically capable of becoming pregnant, unless they are using basic methods ofcontraception during dosing of study treatment and for up to 130 days after lastdose of study drug. Basic contraception methods are defined in Section 4.4.

• Women are considered post-menopausal and not of childbearing potential if theyhave had 12 months of natural (spontaneous) amenorrhea with an appropriateclinical profile (i.e. age appropriate, history of vasomotor symptoms) or havehad surgical bilateral oophorectomy (with or without hysterectomy), totalhysterectomy, or bilateral tubal ligation at least six weeks prior to firstdose of study drug. In the case of oophorectomy alone, only when thereproductive status of the woman has been confirmed by follow up hormone levelassessment is she considered not of childbearing potential. If localregulations deviate from the contraception methods listed above to preventpregnancy, local regulations apply and will be described in the InformedConsent Form (ICF).