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 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 or GFR >30 ml/min by institutional standards (for example 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.

Exclusion criteria

• Concurrent malignancy requiring active concurrent systemic chemotherapy. Hormonal therapy for malignancy and targeted radiation is allowed. If patients after enrollment, have a clinical need for chemotherapy after achieving response on treatment, subjects deriving clinical benefit can be continued on study after discussion with study PI.
• 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 study procedures and/or results
• Active uncontrolled hypertension not responding to blood pressure lowering medications 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 hormone replacement therapy or recent uncontrolled pulmonary embolism or DVT in the last 6 months). Subjects adequately controlled on anticoagulation are permitted.
• Pregnant or nursing women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using basic methods of contraception during dosing of study treatment and for up to 130 days after last dose of study drug. Basic contraception methods are defined in Section 4.4.

• Women are considered post-menopausal and not of childbearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (i.e. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy, or bilateral tubal ligation at least six weeks prior to first dose of study drug. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of childbearing potential. If local regulations deviate from the contraception methods listed above to prevent pregnancy, local regulations apply and will be described in the Informed Consent Form (ICF).