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.