1. Introduction
Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal disease of hematopoietic stem cells caused by somatic cell mutations. The pathological defect of PNH is the abnormal synthesis of glycosyl phosphatidyl inositol (GPI) caused by a PIG-A gene mutation on the X chromosome, which leads to the loss of a group of anchor proteins anchored by GPI on the blood cell membrane, including CD55, CD59 and CD16. The main clinical manifestations are chronic intravascular hemolysis, bone marrow failure, and high-risk complications of thrombosis, etc.[1,2].
With the advent of eculizumab (a recombinant human anti-complement C5 monoclonal antibody), PNH treatment has entered the era of complement pathway inhibition. The efficacy and safety of eculizumab in the treatment of PNH have been confirmed[3-5]. It can reduce the need for blood transfusion, improve anemia, relieve symptoms related to complement-mediated chronic intravascular hemolysis (such as renal function damage), reduce pulmonary hypertension and severe thrombotic events, and ultimately improve quality of life and prolong survival. Moreover, the research and development of many new complement pathway inhibitors (ravulizumab, crovalimab, coversin, etc.)[6-8] have also achieved good therapeutic effects and overcome many shortcomings of eculizumab, which provides new hope for PNH treatment.
Unfortunately, none of the above monoclonal antibodies are currently on the market in China. In addition, these monoclonal antibodies are extremely expensive [9,10]. Therefore, in our country, glucocorticoids are still the first-line drug for controlling hemolytic attack in PNH with definite curative effects. However, the long-term use of glucocorticoids can cause serious adverse reactions, such as hypertension, diabetes, and femoral head necrosis, and some PNH patients are prone to relapse after ineffective or reduced glucocorticoid treatment. Therefore, treatment of refractory/relapsed PNH that is ineffective or dependent on glucocorticoids has always been a difficult problem. In recent years, studies by Cooper et al[11], Lee et al[12] and domestic studies by Wu D et al[13,14] have confirmed that allo-hematopoietic stem cell transplantation (HSCT) has a definite curative effect in PNH patients with transplantation indications, and the prognosis of patients is improving. In 2016, the team of Professor Wu Depei in China reported 18 PNH patients who underwent haplotype-matched HSCT, and the expected 5-year disease-free survival rate was 80.5±10.2% without relapsed cases [13]. The above research results provide hope for the radical cure of refractory/relapsed PNH, but the risk of HSCT is higher, the limited treatment experience and the transplant indications are currently inconclusive and difficult to promote.
Therefore, we designed several chemotherapy regimens to treat some refractory and relapsed PNH patients. As the same dose of chemotherapy is tolerated less well in PNH patients than in leukemia patients, to avoid the risk of excessive bone marrow suppression, we used a low dose and a short course of treatment. PNH is a benign clonal disease, and normal clones and PNH clones coexist in PNH patients. The current treatment involves killing a considerable number of PNH clones with chemotherapy and then using the strong ability to tolerate complement and faster recovery of normal clones compared to PNH clones to promote the gradual replacement of PNH clones with normal clones.
Twenty patients with PNH treated with chemotherapy from June 2010 to June 2020 were enrolled in our study. We analyzed the clinical characteristics of these PNH patients, including the clinical efficacy of chemotherapy, survival, chemotherapy -related adverse reactions and safety.