Effective Management of Polycythemia Vera With Ropeginterferon Alfa-2b Treatment.

Background: Polycythemia vera (PV) is a myeloproliferative neoplasm. Ropeginterferon alfa-2b is a new-generation polyethylene glycol-conjugated proline-interferon. It is approved for the treatment of PV at a starting dose of 100 µg (50 µg for patients receiving hydroxyurea (HU)) and dose titrations up to 500 µg by 50 µg increments. The study was aimed at assessing its efficacy and safety at a higher starting dose and simpler intra-patient dose escalation. Methods: Forty-nine patients with PV having HU intolerance from major hospitals in China were treated biweekly with an initial dose of 250 µg, followed by 350 µg and 500 µg thereafter if tolerated. Complete hematological response (CHR) was assessed every 12 weeks based on the European LeukemiaNet criteria. The primary endpoint was the CHR rate at week 24. The secondary endpoints included CHR rates at weeks 12, 36 and 52, changes of JAK2V617F allelic burden, time to first CHR, and safety assessments. Results: The CHR rates were 61.2%, 69.4% and 71.4% at weeks 24, 36, and 52, respectively. Mean allele burden of the driver mutation JAK2V617F declined from 58.5% at baseline to 30.1% at 52 weeks. Both CHR and JAK2V617F allele burden reduction showed consistent increases over the 52 weeks of the treatment. Twenty-nine patients (63.0%) achieved partial molecular response (PMR) and two achieved complete molecular response (CMR). The time to CHR was rapid and median time was 5.6 months according to central lab results. The CHRs were durable and median CHR duration time was not reached at week 52. Mean spleen index reduced from 55.6 cm2 at baseline to 50.2 cm2 at week 52. Adverse events (AEs) were mostly mild or moderate. Most common AEs were reversible alanine aminotransferase and aspartate aminotransferase increases, which were not associated with significant elevations in bilirubin levels or jaundice. There were no grade 4 or 5 AEs. Grade 3 AEs were reversible and manageable. Only one AE led to discontinuation. No incidence of thromboembolic events was observed. Conclusion: The 250-350-500 µg dosing regimen was well tolerated and effectively induced CHR and MR and managed spleen size increase. Our findings demonstrate that ropeginterferon alfa-2b at this dosing regimen can provide an effective management of PV and support using this dosing regimen as a treatment option.

[Clinical Analysis of Hospitalized Children with Primary Immune Thrombocytopenia].

OBJECTIVE: To investigate the factors affecting the chronicity of childhood primary immune thrombo-cytopenia (ITP) and compare the efficiency of different first-line treatment regimens. METHODS: Children with ITP hospitalized in our hospital from September 2013 to October 2018 were retrospectively analyzed. RESULTS: Three hundred and one children (150 males and 151 females) were included in this study, with a median age of 8 (0.17-17) years old, and 110 (36.5%), 92 (30.6%), and 99 (32.9%) cases were grouped into newly diagnosed, persistent, and chronic ITP, respectively. The median of follow-up was 41.92 (1.07-74.03) months. At the end of the follow-up (October 2019), among the 202 newly diagnosed/persistent ITP children, 79 cases (59 newly diagnosed and 20 persistent ITP) achieved remission within 1 year after initial diagnosis, with a remission rate of 39.3%; 122 cases (50 newly diagnosed and 72 persistent ITP) developed chronic disease, with a chronicity rate of 60.7%; one case underwent splenectomy. In 99 cases with chronic ITP, 5 cases underwent splenectomy. Multivariable logistic regression analysis showed that, the insidious onset of symptoms (OR=3.754, 95%CI: 1.882-7.488, P=0.000) increased the risk of chronicity, while the positive antibody to anti-platelet membrane glycoprotein (OR=0.446, 95%CI: 0.224-0.888, P=0.021) might reduce the risk of chronicity. And no difference was found by the analysis of subtype of anti-platelet membrane glycoprotein (P=0.305). The efficacy of the first-line treatment of intravenous immunoglobulin (IVIG) alone or combined with steroid was better than that of steroid alone (P=0.028, 0.028), however, the efficiency was not significantly different between IVIG alone and combined with steroid (P=0.086). CONCLUSION: Insidious onset of symptoms in pediatric ITP increases the risk of chronicity, while the positive titer of anti-platelet membrane glycoprotein may reduce the risk. In the first-line treatment for the newly diagnosed/persistent children. The efficacy of IVIG alone or combined with steroid is better than that of steroid alone.

[Symptomatic Profiles of 173 Chinese Patients with Essential Thrombocythemia].

OBJECTIVE: To explore the symptomatic burden of patients with essential thrombocythemia (ET) and its relation with clinical characteristics including the mutation status, therapeutic protocols and sex. METHODS: Total of 173 Chinese ET patients were selected and grouped on the basis of disease characteristics (mutation status, therapeutic pro to- cols, and sex). RESULTS: All the groups showed low-to-high symptom burden, with the highest in the Hu (hydroxyurea)-group (total symptom score [TSS], 14.7; range, 7.6-14.7). In the JAK2V617F-positive, Hu-treated, and female groups TSS and independent symptom scores were higher than those in the control group. The CALR-positive and IFN-α-treated groups had lower overall and individual scores as compared with groups lacking the corresponding characteristics. As the number of characteristics (JAK2V617F-positive, Hu-treated, and female) increases, the severity of symptoms gradually increased. CONCLUSION: The different characteristics have various effects on symptom burden in ET patients. The accumulation of certain characteristics will lead to more severe symptom burden, thus the patient＇s symptom burden should be considered comprehensively when making up the treatment schemes and prognosis.

[Clinical Characteristic of "triple-negative" Essential Thrombocythaemia Patients and Mutation Analysis by Targeted Sequencing].

BACKGROUND: Essential thrombocythemia is a subgroup of myeloproliferative neoplasms. Previous studies identified mutations of JAK2, CALR, and MPL that are closely related with the pathogenesis of myeloproliferative neoplasms. All these mutations contribute to the hyperactivation of JAK2/STAT pathway. However, a small proportion of essential thrombocythemia patients does not display such mutations. The pathogenesis of "triple-negative" form of essential thrombocythemia remains unknown. OBJECTIVE: To investigate the clinical characteristics of triple-negative essential thrombocythemia and related mutation genes. METHODS: To identify the mutations associated with triple-negative essential thrombocythemia, next-generation sequencing was used to conduct targeted sequencing of 360 genes in samples from 68 patients. RESULTS: At least one missense mutation was detected in all the patients and all the detected genes. After screening the data, it was observed that 10 genes with the 10 highest mutation were follows: FLT3, SH2B3, ASXL1, ADAMTS1, TET2, TP53, EGFR, CUX1, GATA2, and MPL.When only rare genes (i.e., with a frequency in Asian populations lower than 5%, as estimated by the 1000 Genomes Project) were analyzed, the most frequently mutated genes in the patients were TET2 (33.82%), SH2B3(29.41%), and ASXL1 (23.53%). Our study identified some mutations that did not previously reported. Although all these mutations need further validation, high incidence rates may indicate relevance of the respective mutations to essential thrombocythemia pathogenesis. Some of the detected mutations have been previously reported; these mutations were also found in a large proportion of our subjects. CONCLUSION: whole-exon sequencing can provide a higher level of accuracy for gene mutation analysis and assist in identifying mutations that contribute to illustrate the pathogenesis of essential thrombocythemia.

[Clinical Characteristics and Long-Term Outcome of 125 Chinese Young Patients with Essential Thrombocythemia].

OBJECTIVE: To investigate the clinical characteristics and long-term outcome of Chinese young patients (≤40 years) with essential thrombocythemia(ET), and to develop a thrombosis predicting model specific for young patients with ET, so as to provide a new evidence for risk stratification and treatment. METHODS: Medical records of 125 Chinese young patients with newly diagnosed of ET were retrospectively analyzed. RESULTS: The median age at diagnosis was 32 (18-40) years old, with 37 males and 88 females. During follow-up, 18 patients (14.4%) experienced major thrombotic events. JAK2 V617F (HR=8.895, P=0.001), history of thrombosis (HR=8.001, P<0.001) and WBC≥12.0×109/L (HR=5.225, P=0.002) were independent risk factors for thrombosis. The incidence of thrombosis and risk factors in young patients were different from that in general ET population, so a thrombosis predicting model specific for young patients with ET was developed. In this model, JAK2 V617F (score 2), history of thrombosis (score 2) and WBC≥12.0×109/L (score 1) were used to divide the patients into low risk (score 0), intermediate risk (score 1-2) and high risk (score≥3) groups. These 3 groups exhibited significantly different thrombosis-free survival (χ2=32.223, P<0.001). Antiplatelet treatment could prevent the occurrence of thrombosis (HR=0.081, P<0.001), while cytoreductive agents significantly decreased the risk of thrombosis only in intermediate and high risk groups (14.3% vs 36.4%, χ2=4.416, P=0.036). Seven patients (5.6%) evolved to myelofibrosis, and one of them finally progressed in to acute leukemia. The only risk factor for evolution was WBC≥15.0×109/L (χ2=5.434, P=0.020). Neither antiplatelet treatment nor cytoreductive agents could prevent disease progression. CONCLUSION: The incidence of thrombosis and risk factors in young patients with ET are different from that in general ET population. The thrombosis-predicting model specific for young patients with ET is useful for guiding therapeutic decisions.

[Role of Toll-like receptor 2 in primary immune thrombocytopenia].

The aim of this study was to explore the role of Toll-like receptor (TLR) 2 in primary immune thrombocytopenia (ITP) by detecting TLR2 expression in the peripheral blood lymphocytes of patients with ITP and evaluating the role of TLR2 activation on inflammatory cytokine secretion. A total of 39 ITP patients and 21 normal controls were enrolled in this study. The expression of TLR2 was detected by real-time PCR and flow cytometry, and the concentration of IL-6 and TNF-α in culture supernatant of PBMNC treated with pam3CSK4 for 48 hours were detected by ELISA. The results showed that the expression of TLR2 mRNA in active ITP patients (3.561 ± 0.741) was significantly higher than that in normal controls (1.750 ± 0.314) (P < 0.05), but there was no statistically significant difference between remission ITP patients (2.333 ± 0.448) and normal controls (P > 0.05) . Flow cytometry analysis found that the TLR2 was not expressed on T and B cells, but expressed on all monocytes both from ITP patients and normal controls. Further activation experiment showed that TLR2 activation in vitro could induce the expression of IL-6 (1644 ± 634.0 vs 4111 ± 525.2 pg/ml) and TNF-α (75.37 ± 22.31 vs 326.0 ± 109.9 pg/ml) in PBMNC from ITP patients (both P < 0.05), but just could promote IL-6 expression in normal controls (2119 ± 636.9 vs 4671 ± 315.9 pg/ml)(P < 0.05). It is concluded that the expression of TLR2 mRNA is up-regulated in PBMNC of ITP patients, and this increased TLR2 maybe participate in ITP through inducing secretion of inflammatory cytokines.

[Clinical characteristics of 520 children with hemophilia in a single medical center].

OBJECTIVE: To analyze the clinical characteristics, diagnosis and treatment of pediatric hemophilia in single center over the decade. METHODS: A retrospective study was conducted with 520 hemophilic children hospitalized in our medical center between January 2002 and December 2012. RESULTS: All the patients were male including 438 hemophilia A (HA) and 82 hemophilia B (HB). There were significant differences in APTT between severe and mild- to moderate hemophilia (P<0.05). In pediatric HA and HB, delay time of diagnosis were 1.42 and 1.17 year, respectively. Children of 7-12 years were the largest population of visiting a doctor, and the spontaneous bleeding episode was the main cause. The most common hemorrhage site was soft tissue in early childhood, but joint was increasingly affected with age as children growth. All bleeding sites and frequencies were not associated with plasma factor level of patient (P>0.05). Knee and anKle were mainly involved in early child, while elbow and shoulder were involved increasingly in later childhood. Additionally, in HA and HB, inhibitor occurrence were 8.9%(19/214) and 12.8%(5/39), inducing 78.9%(15/19) and 40.0%(2/5) of high titer inhalator, and antiHCV-positive rate were 2.8%(11/397) and 2.5%(2/79), respectively. CONCLUSION: Our data highlights that delay in diagnosis and blood-borne infections were significantly reduced over the decade, but the development of inhibitor still remains a major challenge with wide-scale usage of factor in replacement therapy.