Luspatercept in Patients Affected With Rare Inherited Anemias

This is a prospective multicenter phase II basket trial evaluating Luspatercept in patients affected with rare inherited anemias including : ✔ CSA group: constitutional non syndromic sideroblastic anemia () due to germline mutation including those with ALAS2, SLC25A38, SLC19A2, GLRX5, HSPA9. and other gene mutations ✔ CDA group: constitutional dyserythropïetic anemias ( (type I and II) ✔ NTD-DBA group: Diamond-Blackfan anemia (DBA) not requiring regular transfusion support (NTD-DBA) with or without continuous steroid therapy); (therapeutic independence or with continuous steroid therapy); 2 subgroups will be considered: RPS19 versus other genetic subgroups (RPL5, RPL11 and RPS26 mutations) ; to note these 4 genotypes account for the vast majority of patients

Patients will be recruited from centers of expertise within the European Union (France and Italy). In total, 45 patients are will be recruited.

Inclusion criteria

• Patient affected with a rare constitutional anemia including. :

• constitutional non syndromic sideroblastic anemia (CSA) including those due to germline mutation in ALAS2, SLC25A38, SLC19A2, GLRX5, HSPA9 and also more rare cases with other mutations. . Patients without genetic diagnosis (currently up to 30% of CSa patients may be included after approval of PI and geneticists
• constitutional dyserythropïetic anemias CDA (type I and II)
• Diamond-Blackfan anemia not requiring regular transfusion support (NTD-DBA) (therapeutic independence or with continuous steroid therapy); 2 subgroups should be considered: RPS19 versus other genetic subgroups (mainly RPL5, RPL11 and RPS26 variants). Inclusions will be considered in order to have at least 3 patients in each subgroup before to expand inclusions
• For diseases of the three subtypes (CSA, CDA, and DBA-NTD), diagnosis must be supported genetically by presence of ACMG class 4 or 5 variant(s).
• Age ≥18 years at the first screening
• For CSA and CDA, both Transfusion dependent (TD) patients and Non Transfusion dependent (TD) patients may be included:

• TD patients: transfusion-dependency definition is: 6 to 20 units of packed red cells within previous 24 weeks with no transfusion-free period of > 56 days (except for DBA patients for whom transfusion dependency is a factor of exclusion)
• NTD patients: patients must have significant anemia e.g. hemoglobin < 10.5 gr/dl (average of at least 2 Hb measurements separated by a minimum of 7 days during screening period) occasional transfusion aloowed if ≤ 5 red-cell units per 24 weeks and red blood cell transfusion free > 8 weeks before inclusion
• Adequate renal function, defined by creatinine less than 1.5 times the upper limit of normal, creatinine clearance ≥ 30 mL/min (MDRD formula).
• Adequate liver function, defined by transaminases and gamma-glutamyl transferase less than 1.5 times the upper limit of normal.
• ECOG performance status 0-2 at the time of screening.
• Be willing and able to give written informed consent and to comply to all study procedures for the duration of the study.
• A FCBP (female of childbearing potential) for this study was defined as a sexually mature woman who: (1) had not undergone a hysterectomy or bilateral oophorectomy; or (2) had not been naturally postmenopausal (amenorrhea following cancer therapy did not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months). A FCBP participating in the study must:

• Have had 2 negative pregnancy tests as verified by the investigator prior to starting the Investigational Product (IP) (unless the screening pregnancy test was done within 72 hours of Cycle 1 Day 1). She must have had agreed to ongoing a monthly pregnancy testing during the course of the study and after EOT
• If sexually active, agreed to have used, and been able to comply with, highly effective contraception** without interruption, 5 weeks prior to starting IP, during treatment with IP (including dose interruptions), and for 12 weeks after discontinuation of IP. ** Highly effective contraception was defined in this protocol as the following (information also appeared in the ICF): Hormonal contraception (eg, birth control pills, injection, implant, transdermal patch, vaginal ring), intrauterine device, tubal ligation (tying your tubes), or a partner with a vasectomy
• Male subjects must: Have agreed to use a condom, defined as a male latex condom or nonlatex condom NOT made out of natural (animal) membrane (eg, polyurethane), during sexual contact with a pregnant female or a FCBP while participating in the study, during dose interruptions, and for at least 12 weeks following IP discontinuation, even if he had undergone a successful vasectomy

Exclusion criteria

• DBA patients with transfusion dependency or DBA patients with non RPS19, RPS26, RPL5 or RPL11 genotype or without gene identification
• For patients with CSA and no established genetic diagnosis, acquired sideroblastic anemia and SF3B1 variant should be excluded with non RPS19, RPS26, RPL5 or RPL11 genotype or without gene identification
• Severe infection or any other uncontrolled severe condition.
• Uncontrolled hypertension
• Significant cardiac disease - NYHA Class III or IV or having suffered a myocardial infarction in the last 6 months.
• Use of investigational agents within 30 days or any anticancer therapy (including IMiD) within 2 weeks before the study entry. The patient must have recovered at least a grade 1 from all acute toxicity from any previous therapy.
• Use of EPO within 4 weeks of study entry
• Active cancer or cancer during the year prior to trial entry other than basal cell carcinoma, or carcinoma in situ of the cervix or breast.
• Patient already enrolled in another therapeutic trial of an investigational drug.
• Known HIV infection or active hepatitis B or C.
• Women who are or could become pregnant or who are currently breastfeeding.
• Any medical or psychiatric contraindication that would prevent the patient from understanding and signing the informed consent form.
• Patient eligible at short or medium term for allogeneic stem cell transplantation.
• Known allergies to luspatercept or any of its excipients.
• No affiliation to a health insurance system
• For men and women of reproductive potential: unwillingness to be abstinent or use double anticonception during the trial period.
• Persons deprived of liberty by judicial or administrative decision
• Persons subject to a legal protection measure (guardianship, curatorship, safeguard of justice)