Open-Label, Phase II Trial of Isatuximab for Patients With Refractory Immune Cytopenias After Allogeneic Hematopoietic Cell Transplantation

Inclusion Criteria:

• Age ≥ 18 years (There are no dosing/AE data for isatuximab in children).

• Disease for which patient underwent an allo-HCT is in documented remission.

• Patients must have previously had documented primary neutrophil and plateletengraftment, defined as:

• Neutrophil engraftment: the first of 3 successive days with an absoluteneutrophil count of ≥500/μL after post-transplantation nadir.

• Platelet engraftment: the first of 3 consecutive days with a platelet count of 20,000/μL or higher in the absence of platelet transfusion for 7 consecutivedays.

• Patients must be at least 45 days post allogeneic HCT to enroll.

• Patients must be diagnosed with IC(s) based on the following criteria: o For AIHA: Positive (abnormal) DAT test and decreasing hemoglobin of ≥2 g/dL from astable baseline (i.e., from the patients typical hemoglobin value prior to AIHA) andat least grade 2 (i.e., hemoglobin <10 g/dL) due to evidence of hemolytic anemiawith ≥2 of the following tests: increased reticulocyte count (>ULN), increasedlactate dehydrogenase (LDH) (>ULN), decreased haptoglobin (<LLN), increasedunconjugated bilirubin (>ULN).

• DAT negative AIHA may be included providing exclusion of alternative etiology ofhemolytic anemia.

• For ITP: decreasing thrombocytopenia from baseline (i.e., from the patientstypical platelet count prior to ITP) and platelet count ≤30 K/µL or requiringplatelet transfusions in the absence of other causes of thrombocytopenia (including drug-induced thrombocytopenia), and with normal or increased bonemarrow megakaryocytes.

• For PRCA: severe anemia (hemoglobin <8 g/dL without transfusions) withreticulocytopenia (reticulocyte percentage <1% and/or absolute reticulocytecount <10,000/µL) after exclusion of obvious causes of anemia.

• Patients with concomitant ICs can be enrolled on the study.

• Patient must have responded incompletely to their previous treatment, defined as:

• Corticosteroid refractoriness: defined as a clear progression or minimalresponsiveness of IC(s) after ≥7 days of treatment with prednisone equivalentof ≥1 mg/kg/day.

• Corticosteroid dependence: defined as dependence on prednisone equivalent of ≥0.5 mg/kg/day to maintain hemoglobin level ≥2 g/dL nadir level (for AIHAand/or PRCA), and/or platelet count ≥30 x 109/L or ≥2-fold increase from nadirlevel (for ITP).

• Refractory IC(s) after ≥2 treatment lines including corticosteroids (≥0.5mg/kg/day prednisone equivalent), IVIG (400 mg/kg/day for 2 to 5 days), and/orrituximab, etc.

• For rituximab treated patients, refractoriness will be defined as no orminimal response within 2 weeks of completing ≥4 doses of rituximab.

• Absolute neutrophil count (ANC) ≥ 1.0 x 109/L. o Growth factors, including granulocyte colony stimulating factors anderythropoietin are allowed, but should be administered at a stable dose.

• No active hepatitis viral infection or on active treatment for hepatitis infection.

• Female patients of childbearing potential are eligible if the patient has had anegative serum or urine pregnancy test within 10-14 days prior to startingisatuximab therapy.

They must also agree to avoid pregnancy by using an adequate method of contraception (2 barrier method or 1 barrier method with a spermicide or intrauterine device) for 2 weeks prior to screening, during and 5 months after the last dose of trial medication. Adequate methods of contraception are provided as examples. Other acceptable and effective methods of birth control are also permitted (e.g., abstinence).

• Male patients must agree to not donate sperm while on the study and for at least 5months after the last dose of study drug. They must agree to use contraceptionduring the intervention period and for at least 5 months after the last dose ofisatuximab treatment.

• Subjects must be able to give informed consent.

Exclusion Criteria:

• Presence of relapse/progression of malignant disease for which the patient underwentallo-HCT

• Patients with anemia and/or thrombocytopenia related to transplant-associatedthrombotic microangiopathy.

• Patients with active GVHD requiring therapy may be eligible if the GVHD isresponsive to treatment (< grade 4 in severity), and after agreement between thesponsor and principal investigator.

• Organ insufficiency based on above criteria.

• Pregnancy or unwillingness to agree to birth control as noted above.

• Known to be HIV+ or to have active hepatitis A, B, or C infection (i.e., withviremia).

Of note:

• Patients can be eligible if anti-HBc seropositive (with or without positiveanti-HBs), but HBsAg and HBV DNA are negative.

• Patients with antiviral therapy for HCV started before initiation of treatment andpositive Hep C antibodies are eligible. The antiviral therapy for Hep C shouldcontinue throughout the treatment period until seroconversion. Patients withpositive anti-Hep C and undetectable Hep C RNA without antitviral therapy for Hep Care eligible.

• Any clinically significant, uncontrolled medical condition(s), includinginfection(s) that, in the Investigator's opinion, would expose the patient toexcessive risk or may interfere with compliance or interpretation of the studyresults.

• Hypersensitivity or history of intolerance to steroids, mannitol,pregelatinized starch, sodium stearyl fumarate, histidine (as base andhydrochloride salt), arginine hydrochloride, poloxamer 188, sucrose, prioranti-CD38 moAb such as daratumumab, or any of the other components of studyintervention that are not amenable to premedication with steroids and H2blockers or would prohibit further treatment with these agents.

• Received any investigational drug within 14 days or 5 half-lives of theinvestigational drug prior to initiation of study intervention, whichever islonger. In case of very aggressive disease (e.g., acute leukemia) delay couldbe shortened after agreement between sponsor and principal investigator, inabsence of residual toxicities from previous therapy.

• Patients on post-HCT maintenance therapy to reduce the risk of relapse (for patientswith hematologic malignancies) or GVHD (e.g., FLT3 inhibitors, etc.) may be eligibleafter agreement between the sponsor and principal investigator.

• Contraindication to any concomitant medication, including pre-medications orhydration given prior to therapy

• Participants who are unable to consent to the study or comply with the studyprocedures.