4. Discussion
PNH is one of the most common hemolytic anemias in northern China. According to the reported cases in papers. In our country, the traditional treatment for PNH still focus on ”protecting” PNH clones, reducing complement attack and destruction, and reducing hemolysis. Glucocorticoids are still effective drugs for reducing hemolysis to control PNH. After years of clinical progress, the current use of glucocorticoids and hematopoietic therapy has allowed the remission rate of the disease reach more than 60%, but nearly 40% of patients are not sensitive to this treatment[16,17]. Even in patients who achieve remission after treatment, there is still more than a 10% possibility of relapse[18].
At the end of the 1970s, Soviet scholars reported that cyclophosphamide or 6-mercaptopurine achieved certain effects in the treatment of PNH[19]. In our previous study[20], we found that the expression rates of G-CSFR and SCFR on CD34+CD59+ cells of PNH patients were significantly lower than those on CD34+CD59+ cells, while there was no significant difference in the expression of G-CSFR and SCFR between CD34+CD59+ cells of PNH patients and healthy controls. These results suggest that the response of mutated hematopoietic stem/progenitor cells from PNH patients to stimulation with G-CSF and SCF may be reduced due to the insufficient expression of G-CSF and SCFR. In a follow-up study[20], we confirmed that the MFI of p-stat5 in CD34+CD59+ cells was significantly higher than that in CD34+CD59+ cells before and after G-CSF or SCF stimulation based on protein phosphorylation flow cytometry, and the MFI of phosphorylated STAT5 in CD34+CD59+ cells of PNH patients was significantly higher than that in CD34+CD59+ cells of PNH patients after G-CSF or SCF stimulation. However, the proliferation of abnormal clones was not significant, which widened the gap between normal hematopoietic cells and abnormal PNII cells and restored normal hematopoiesis.
Chemotherapy can kill both PNH clones and normal clones, but normal clones have faster proliferation rates and higher expression of CD114 and CD117 on their surface than PNH clones. After G-CSF stimulation, normal clones are more reactive than PNH clones, so normal clones are dominant, and the symptoms of patients disappear or are reduced. PNH patients have GPI-AP deletions other than CD55 and CD59.Our previous research results[21-23] have proven that chemotherapy can effectively reduce the PNH clonal load, control hemolysis, improve anemia, and greatly reduce the level of corticosteroids and is thus a promising treatment. In this study, we retrospectively analyzed the efficacy and safety of reduced-dose combined chemotherapy in 20 patients with refractory/relapsed PNH.
All patients enrolled in the study had refractory/relapsed PNH, 1 mg/kg/d prednisone was ineffective for more than 1 month, or adrenal glucocorticoid treatment was effective, but relapse occurred soon after a dose reduction. Among the 20 patients with PNH, 17 had a marked improvement in anemia after chemotherapy, 14 patients stopped blood transfusion, and Hb in 3 patients rose to normal levels. Although 6 patients did not stop blood transfusion, the transfusion interval was significantly prolonged. The percentages of LDH, TBIL and RET, which are indicators of hemolysis, were significantly lower than those before chemotherapy. The above results confirmed that after chemotherapy with reduced-dose DA or HA regimens, the hemolysis index of PNH patients was significantly improved, PNH clones were reduced, and the dosage of adrenal glucocorticoids was reduced by more than half compared with that before chemotherapy.
Our study also found that the 10-year overall survival of patients from diagnosis to the end of follow-up was 78.29%. We used multivariate regression to analyze the effects of sex, age, LDH elevation, and PNH clone ratio on survival. The results showed that the above factors had no statistically significant impact on OS, which may be related to the number of samples in each group in our study. In future research, it will be necessary to increase the number of samples and conduct an in-depth analysis of the above factors.
Of the 17 patients with PNH for whom chemotherapy was effective, 6 patients relapsed within 2 years, and 2 patients relapsed twice within 1 year, which suggests that low-dose chemotherapy did not eradicate PNH clones. Of the remaining 9 patients, 7 patients did not relapse after observation for 1 year, and 4 patients did not relapse after observation for 2 years. The above results indicate that reduced-dose chemotherapy cannot eradicate PNH clones, but it can inhibit PNH clones to a great extent. The long-term efficacy of low-dose chemotherapy needs to be further observed with an expanded sample size.
The development and launch of eculizumab and new complement pathway inhibitory drugs have brought new hope for the treatment of PNH[24-27]. Since the above drugs have not yet been marketed in our country, new treatment methods urgently need to be identified. Our results confirm that reduced-dose chemotherapy combined with hematopoietic growth factors, component blood infusion, and symptomatic supportive therapy can effectively reduce PNH clones, reduce hemolytic attacks, and stabilize the disease. This is currently a promising and widely used therapeutic method.