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.