Clinical trial NCT05559827: Efficacy of the antiCD38 Monoclonal Antibody Isatuximab in the Treatment of PCRA by Major ABO Mismatch After Allogeneic Hematopoietic Stem Cell Transplantation
Official title: Randomized Prospective Trial Evaluating the Efficacy of the antiCD38 Monoclonal Antibody Isatuximab in the Treatment of PCRA by Major ABO Mismatch After Allogeneic Hematopoietic Stem Cell Transplantation
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE2
Conditions: Immunological Pure Red Cell Aplasia
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2022-09-29
Enrollment: 90
Sex: ALL
Minimum age (years): 15
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: A quarter of allogeneic hematopoietic stem cell transplantation are performed in a situation of major ABO mismatch exposing patients to the risk of immunological pure red cell aplasia (PRCA) after transplant. PCRA after transplant is defined as anemia with low reticulocytes count (under 10 G/L) after day 60 despite good leucocytes and platelet engraftment, full donor chimerism, associated with the persistence of recipients hemagglutinins (anti-A or anti-B antibodies). Bone marrow evaluation when performed show erythroid hypoplasia. Red blood cells transfusions are necessary every two weeks until remission leading to impaired quality of life (anemia, repeated hospitalization), iron overload, and need for iron chelation therapy. Treatments currently used are inefficient (anti CD20 monoclonal antibodies, EPO, steroids, plasma exchanges, proteasome inhibitors) or at risk of severe acute GVHD (donor lymphocytes infusion). PRCA has been demonstrated to be associated with the persistence of recipient's plasma cells.

Anti-CD38 monoclonal antibodies which targets plasma cells secreting hemagglutinins responsible of PCRA are a promising treatment: 6 cases reported in the literature support a rapid and sustain efficacy but a prospective randomized evaluation of its efficacy and safety in this context is necessary.

The main objective of the study is to assess the efficacy of the treatment of PRCA by isatuximab after allogeneic hematopoietic stem cell transplant compared to supportive care only control group (reduction in PRCA resolution time in days)


Eligibility criteria: Inclusion Criteria:

* Aged 15 years or older
* Having receiving an allogeneic hematopoietic stem cell transplantation in condition of major ABO mismatch
* PCRA defined by persistent red blood cell transfusion dependence at day 60 post-transplant with reticulocytes count under 10 G/L despite full donor chimerism and a good leucocytes (\>1 G/L) and platelet (\>50G/L) recovery
* No relapse or progression of underlying disease
* Contraception methods must be prescribed during all the duration of the research and using effective contraceptive methods during treatment for women of childbearing age (continue abstinence from heterosexual intercourse is accepted) and for man during the study treatment period and for at least 5 months after the last dose of study treatment and refrain from donating sperm during this period
* With health insurance coverage
* Having signed a written informed consent (2 parents for patients aged less than 18)

Exclusion Criteria:

* Aged \< 15 years
* Relapse of underlying disease
* Leucocyte chimerism \< 95%
* PRCA related to Parvovirus B19 infection (positive blood PCR)
* Known to be HIV+ or to have hepatitis A, B, or C active infection
* Active tuberculosis
* Pregnancy (βHCG positive) or breast-feeding.
* Patient receiving recombinant human erythropoietin.
* Patient receiving proteasome inhibitor (Bortezomib for example).
* Patient receiving thrombopoietin receptor agonists (ARTPO).
* Patient receiving plasma or plasmapheresis exchanges after transplant.
* Planned to receive any investigational drug within 14 days or 5 half-lives of the investigational drug, whichever is longer.
* Any clinically significant, uncontrolled medical conditions that, in the Investigator's opinion, would expose excessive risk to the patient or may interfere with compliance or interpretation of the study results.
* Hypersensitivity to the active substance or history of intolerance to steroids, mannitol, pregelatinized starch, sodium stearyl fumarate, histidine (as base and hydrochloride salt), arginine, hydrochloride, poloxamer 188, sucrose or any of the other components of study therapy that are not amenable to premedication with steroids and H2 blockers or would prohibit further treatment with these agents.
* Who have any debilitating medical or psychiatric illness
* Under tutorship or curatorship
* Who not understand informed consent for an optimal treatment and follow-up

Primary outcomes:
measure: time interval between randomization (corresponding to the M6 post-transplant) and resolution of PRCA (date of resolution of reticulocytopenia) treated or not by the anti-CD 38 monoclonal antibody isatuximab
timeFrame: 9 months post randomization
Secondary outcomes:
measure: Number of red blood cell transfusions after randomization
timeFrame: from randomization through study completion, an average of 9 months after randomization
measure: Ferritin levels
timeFrame: at month 6 post-transplant
measure: Ferritin levels
timeFrame: at month 9 post-transplant
measure: Ferritin levels
timeFrame: at month 15 post-transplant
measure: Adverse events (CTC-AE grade ≥ 2)
timeFrame: up to 13 months post transplant
measure: Quality of life questionnaire (EORTC QLQ-C30- v3)
timeFrame: at day 60
measure: Quality of life questionnaire (EORTC QLQ-C30- v3)
timeFrame: at day 100
measure: Quality of life questionnaire (EORTC QLQ-C30- v3)
timeFrame: at 6 months
measure: Quality of life questionnaire (EORTC QLQ-C30- v3)
timeFrame: at 9 months
measure: Quality of life questionnaire (EORTC QLQ-C30- v3)
timeFrame: at 12 months
measure: Quality of life questionnaire (EORTC QLQ-C30- v3)
timeFrame: at 15 months post-transplant
measure: Spontaneous resolution of PRCA between day 60 and 6 months post-transplant
timeFrame: at 6 months post-transplant
measure: Antibody level (anti A and/or anti B titers)
timeFrame: at day 60 post transplant
measure: Antibody level (anti A and/or anti B titers)
timeFrame: at day 100 post transplant
measure: Antibody level (anti A and/or anti B titers)
timeFrame: at day 15 post randomization
measure: Antibody level (anti A and/or anti B titers)
timeFrame: at day 29 post randomization
measure: Antibody level (anti A and/or anti B titers)
timeFrame: at day 45 post randomization
measure: Antibody level (anti A and/or anti B titers)
timeFrame: at month 3 post randomization
measure: Antibody level (anti A and/or anti B titers)
timeFrame: at month 6 post-randomization
measure: Antibody level (anti A and/or anti B titers)
timeFrame: at month 9 post-randomization
measure: Number of days of hospitalization
timeFrame: up to 9 months post ranomization
measure: Number of days of transfusions support
timeFrame: up to 9 months post randomization
measure: Number of days of chelation treatments
timeFrame: up to 9 months post randomization
Other outcomes:
Locations:
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