Refractoriness to platelet transfusion is a major problem in a small group of patients, and large-scale manufacturing of clinical grade functional platelets ex vivo has remained an elusive goal. Sugimoto et al report on the results of the first clinical trial of an autologous transfusion of induced pluripotent stem cell (iPSC)-derived platelets in a patient who had severe aplastic anemia but no compatible platelet donor. Using methodology described in a complementary article in Blood Advances, the results provide proof-of-principle and illustrate the challenges to be faced in taking this approach further.

Donor-derived platelets are used to treat or prevent hemorrhage in patients with thrombocytopenia. However, ∼5% or more of these patients are complicated with alloimmune platelet transfusion refractoriness (allo-PTR) due to alloantibodies against HLA-I or human platelet antigens (HPA). In these cases, platelets from compatible donors are necessary, but it is difficult to find such donors for patients with rare HLA-I or HPA. To produce platelet products for patients with aplastic anemia with allo-PTR due to rare HPA-1 mismatch in Japan, we developed an ex vivo good manufacturing process (GMP)–based production system for an induced pluripotent stem cell–derived platelet product (iPSC-PLTs). Immortalized megakaryocyte progenitor cell lines (imMKCLs) were established from patient iPSCs, and a competent imMKCL clone was selected for the master cell bank (MCB) and confirmed for safety, including negativity of pathogens. From this MCB, iPSC-PLTs were produced using turbulent flow bioreactors and new drugs. In extensive nonclinical studies, iPSC-PLTs were confirmed for quality, safety, and efficacy, including hemostasis in a rabbit model. This report presents a complete system for the GMP-based production of iPSC-PLTs and the required nonclinical studies and thus supports the iPLAT1 study, the first-in-human clinical trial of iPSC-PLTs in a patient with allo-PTR and no compatible donor using the autologous product. It also serves as a comprehensive reference for the development of widely applicable allogeneic iPSC-PLTs and other cell products that use iPSC-derived progenitor cells as MCB.

Rapidly progressive interstitial pneumonias (RPIPs) associated with clinically amyopathic dermatomyositis (CADM) are highly resistant to therapy and have a poor prognosis. Multimodal therapies, including direct hemoperfusion using a polymyxin B-immobilized fiber column (PMX-DHP), have a protective effect on RPIPs. We evaluated the effects of PMX-DHP on CADM-associated RPIPs. We retrospectively enrolled 14 patients with CADM-associated RPIPs and acute respiratory failure treated with PMX-DHP, corticosteroids, and immunosuppressive agents. Clinical manifestations were compared between survivors and non-survivors at 90 days after PMX-DHP. The survival rate at 90 days after PMX-DHP was 35.7% (5/14). Before PMX-DHP, the survivor group exhibited a significantly higher PaO2/FiO2 (P/F) ratio and serum surfactant protein-D (SP-D) levels and significantly lower lactate dehydrogenase (LDH) and ferritin levels than the non-survivor group. Platelet counts were significantly decreased after PMX-DHP therapy in both groups, but remained higher in the survivor group than the non-survivor group over the course of treatment. Anti-melanoma differentiation-associated gene 5 (MDA-5) antibody positive patients demonstrated a poor 90-day survival rate, lower platelet counts and P/F ratio, and higher LDH levels than anti-MDA-5 antibody negative patients. CADM-associated RPIPs with anti-MDA-5 antibody is associated with a very poor prognosis. A higher P/F ratio and SP-D level, lower LDH and ferritin levels, higher platelet counts, and anti-MDA-5 antibody negativity are important prognostic markers in patients with CADM-associated RPIPs treated with PMX-DHP.