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.

CAG regimen for refractory or relapsed adult T-cell acute lymphoblastic leukemia: A retrospective, multicenter, cohort study.

Adult patients with relapsed or refractory T-cell acute lymphoblastic leukemia (R/R-T-ALL) have extremely poor prognosis, representing an urgent unmet medical need. Finding an optimal salvage regimen to bridge transplantation is a priority. The CAG (cytarabine, aclarubicin, and G-CSF) regimen was initially used by one group in China, showing unexpectedly promising results in 11 R/R-T-ALL patients. Here, we report the multicenter results of 41 patients who received the CAG regimen as salvage therapy. After one cycle of the CAG regimen, complete remission and partial remission were achieved in 33 (80.5%) and two (4.9%) patients, respectively. Failure to respond was observed in six patients (14.6%). Early T-cell precursor (ETP) (n = 26) and non-ETP (n = 15) patients had a similar CR rate (80.8% vs 80.0%, P = .95). Among 41 patients, allo-HSCT was successfully performed in 27 (66%) patients (22 in CR and 5 in non-CR). With a median follow-up time of 12 months, the estimated 2-year overall survival and event-free survival were 68.8% (95% CI, 47.3%-83.0%) and 56.5% (95% CI, 37.1%-71.9%), respectively. The CAG regimen was well-tolerated, and no early death occurred. Our multicenter results show that the CAG regimen is highly effective and safe, representing a novel choice for adult patients with R/R-T-ALL and providing a better bridge to transplantation.

SETD2 deficiency accelerates MDS-associated leukemogenesis via S100a9 in NHD13 mice and predicts poor prognosis in MDS.

SETD2, the histone H3 lysine 36 methyltransferase, previously identified by us, plays an important role in the pathogenesis of hematologic malignancies, but its role in myelodysplastic syndromes (MDSs) has been unclear. In this study, low expression of SETD2 correlated with shortened survival in patients with MDS, and the SETD2 levels in CD34+ bone marrow cells of those patients were increased by decitabine. We knocked out Setd2 in NUP98-HOXD13 (NHD13) transgenic mice, which phenocopies human MDS, and found that loss of Setd2 accelerated the transformation of MDS into acute myeloid leukemia (AML). Loss of Setd2 enhanced the ability of NHD13+ hematopoietic stem and progenitor cells (HSPCs) to self-renew, with increased symmetric self-renewal division and decreased differentiation and cell death. The growth of MDS-associated leukemia cells was inhibited though increasing the H3K36me3 level by using epigenetic modifying drugs. Furthermore, Setd2 deficiency upregulated hematopoietic stem cell signaling and downregulated myeloid differentiation pathways in the NHD13+ HSPCs. Our RNA-seq and chromatin immunoprecipitation-seq analysis indicated that S100a9, the S100 calcium-binding protein, is a target gene of Setd2 and that the addition of recombinant S100a9 weakens the effect of Setd2 deficiency in the NHD13+ HSPCs. In contrast, downregulation of S100a9 leads to decreases of its downstream targets, including Ikba and Jnk, which influence the self-renewal and differentiation of HSPCs. Therefore, our results demonstrated that SETD2 deficiency predicts poor prognosis in MDS and promotes the transformation of MDS into AML, which provides a potential therapeutic target for MDS-associated acute leukemia.

Clinical Features and Prognosis Analysis of Hodgkin Lymphoma: A Multicenter Retrospective Study Over a Decade of Patients in China.

OBJECTIVE: There is little information available regarding Chinese patients with Hodgkin lymphoma (HL). We analyzed the clinical features, outcome, and prognostic factors of Chinese patients with HL, aiming to establish a new risk model for better risk-adapted therapeutic strategy. PATIENTS AND METHODS: Patients with newly diagnosed HL at 4 medical centers from January 2000 to August 2014 were recruited. RESULTS: A total of 150 patients were reviewed. The median age was 30 years (range, 15-91 years). At completion of initial therapy, 73.65% of patients achieved complete remission. The 5-year event-free survival (EFS) of the entire cohort was 61.1%, the overall survival was 84.7%, and the disease-free survival was 78.8%. B symptoms, extranodal involvement, and International Prognostic Score ≥ 3 remained as independent prognostic factors of EFS. Patients who failed to reach complete remission on interim positron emission tomography/computed tomography or computed tomography had a significantly worse outcome than those who did. A new risk model incorporating traditional risk factors and interim response stratified patients into 3 classes, with a 5-year EFS of 100%, 83.1%, and 33.1%, respectively (P < .0001). CONCLUSIONS: General clinical features were comparable with those of Western patients, whereas therapeutic outcomes were slightly inferior. The novel risk assessment model showed potential as a more powerful prognostic tool by identifying 3 subsets of patients with significantly distinct outcomes, which warrants further validations.

Clinical significance of CSF3R, SRSF2 and SETBP1 mutations in chronic neutrophilic leukemia and chronic myelomonocytic leukemia.

Chronic neutrophilic leukemia (CNL) and chronic myelomonocytic leukemia (CMML) are rare hematologic neoplasms. We performed CSF3R, SRSF2 and SETBP1 mutational analyses in 10 CNL and 56 CMML patients. In this sample cohort, 80% of CNL patients harbored CSF3R mutations, of which the CSF3R T618I mutation was dominant. Mutations in CSF3R and SETBP1 were found in 7.1% and 5.3% CMML patients respectively, while 25% of CMML patients carried SRSF2 mutations. Strikingly, we identified that all of the CSF3R mutations detected in CMML patients were represented by a P733T mutation. The CSF3R P733T mutation represents a novel CSF3R mutation. In addition, none of the four CSF3R P733T mutated patients carried SRSF2 mutations [0/14 (0%) patients with combined CSF3R P733T and SRSF2 mutations vs. 4/42 (9.5%) with CSF3R P733T and wt SRSF2, P < 0.001]. Both mut SRSF2 and mut SETBP1 patients had shorter overall survival (OS) and progression-free survival (PFS) compared to patients with wt SRSF2 (P < 0.001 both) and wt SETBP1 (P < 0.001 and P = 0.02, respectively). While we found no significant differences in OS and PFS as a consequence of CSF3R mutation status, our work suggest that the CSF3R T618I mutation is a diagnostic marker with good specificity and sensitivity for CNL. In conclusion, our study highlights effective diagnostic and prognostic markers of CNL and CMML patients in the Chinese population.

[Treatment of two chronic myeloid leukemia patients with V299L mutation by using nilotinib].

This study was aimed to enhance clinical understanding the effect of nilotinib on CML patients with V299L mutation who were resistant to imatinib. Bone marrow specimens from 2 cases of CML with V299L mutation were collected before and after the treatment with nilotinib. ABL mutation was detected by nested reverse transcription polymerase chain reaction (PCR) followed by direct sequencing. The clinical characteristics of the two cases were analyzed. The results showed that both cases were resistant to imatinib presented V299L mutation. Out of them 1 case achieved complete haematological response (CHR) after treatment with nilotinib for 6 months and another case abstained obvious molecular response after using nilotinib for 7 month. V299L mutation of both cases was turned into negative after the treatment with nilotinib. It is concluded that the nilotinib can safely and effectively override tyrosine kinase inhibitor (TKI) resistance mediated by the V299L mutation. The safety and efficacy of nilotinib for treatment of CML patients with TKI resistance and V299L mutation are satisfactory.

High-dose idarubicin plus busulfan as conditioning regimen to autologous stem cell transplantation: promising post-remission therapy for acute myeloid leukemia in first complete remission?

The optimal post-remission therapy (PRT) for acute myeloid leukemia (AML) remains uncertain. We reported 32 AML patients in first complete remission (CR1) undergoing autologous hematopoietic stem cell transplantation (ASCT) with a characteristic conditioning regimen, termed I-Bu, based on high-dose idarubicin plus busulfan, which considerably strengthened antileukemic activity. Most patients were in better or intermediate-risk group except that cytogenetic or molecular risk information was missing for 18.7 % of the patients. Unpurged peripheral blood stem cells were used in all the cases. The adverse effects were mild and reversible. Only one case of transplant-related mortality was observed. All the patients in this study acquired hematopoietic reconstitution after ASCT. After a median follow-up of 30 (6-119) months, 24 patients (75.0 %) were alive in which 20 (62.5 %) patients were in continuous CR. There were 11 (34.4 %) patients who relapsed after HSCT. Cumulative relapse probability was about 40 % after 24 months. Median OS and DFS have not been reached. Patients in the better and intermediate-risk group had different clinical outcomes, but the differences were not statistically significant. ASCT with I-Bu regimen is possibly promising PRT for better and intermediate-risk AML patients in CR1.

[SRSF2 mutation in patients with chronic myelomonocytic leukemia].

OBJECTIVE: To investigate SRSF2 mutations in patients with chronic myelomonocytic leukemia (CMML) and the clinical characteristics of patients with SRSF2 mutants. METHODS: In this study, the frequency of SRSF2 mutation in a cohort of 20 patients with CMML was detected by polymerase chain reaction (PCR) followed by direct sequencing to couple with their clinical features. RESULTS: Of 20 patients, 4 patients were found harboring SRSF2 mutations, including 2 P95L, 1 P95H and 1 P95R point mutations. There were no significantly statistical differences in terms of their clinical characteristics between mutant and wild type group. CONCLUSION: SRSF2 mutation was not frequently occurred in CMML patients and might associated with poor prognosis. It might be a practically diagnostic maker and therapeutic target in CMML.

[Efficacy of dasatinib in treatment of imatinib-resistant BCR/ABL positive leukemia].

This study was aimed to evaluate the efficacy and safety of dasatinib in BCR/ABL positive leukemia patients with primary or secondary resistance to imatinib. 27 patients with primary or secondary imatinib-resistant chronic myelogenous leukemia (CML) or Philadelphia chromosome positive acute lymphocytic leukemia (Ph(+) ALL) received 100 - 140 mg/d dasatinib orally. Their overall survival and tolerance were evaluated. The results showed that the median duration of dasatinib therapy was 8 (1-66) months in the 27 imatinib-resistant BCR/ABL positive leukemia cases, with a median follow-up of 54 (3-75) months. After the dasatinib treatment, 88.8% of all the 27 cases achieved complete hematologic response (CHR), 29.6% of them achieved major cytogenetic response (mCyR), 37% of all achieved complete cytogenetic response (CCyR) and 18.5% cases achieved major molecular response (MMR). Patients who received dasatinib in progress of disease (CML-AP, CML-BC and bone marrow relapse Ph(+) ALL) had a lower CCyR rate than those in stable disease (CML-CP and bone marrow remission Ph(+) ALL) (P = 0.0377), and 3 - 4 grade adverse events occurred more frequently in progress of disease than that in stable disease. Overall survival of the patients who achieved CCyR after dasatinib therapy was statistically longer than those who did not achieve CCyR (63 m vs 9 m, P = 0.0126). The most common grade 3 - 4 adverse events during dasatinib therapy including hematology events such as thrombocytopenia (51.8%), neutropenia (48.1%), anemia (33.3%), and non-hematologic events such as pleural effusion (18.5%), pulmonary infection (18.5%), pericardial effusion (11.1%). The 3-4 grade adverse events occurred within 12 months from dasatinib therapy, and were mainly observed in patients with progress of disease. It is concluded that dasatinib is an effective drug in imatinib-resistant BCR/ABL positive leukemia patients, the better curative effect and better tolerance has been observed in patients who received dasatinib in stable disease.

Molecular analysis of patients with polycythemia vera or essential thrombocythemia receiving pegylated interferon α-2a.

Pegylated interferon α-2a (PEG-IFN-α-2a) has previously been shown to induce hematologic and molecular responses in patients with polycythemia vera (PV) or essential thrombocythemia (ET). Here we present a follow-up of a phase 2 trial with PEG-IFN-α-2a treatment in 43 PV and 40 ET patients with detailed molecular analysis. After a median follow-up of 42 months, complete hematologic response was achieved in 76% of patients with PV and 77% of those with ET. This was accompanied by complete molecular response (CMR) (ie, undetectable JAK2V617F) in 18% and 17%, of PV and ET patients, respectively. Serial sequencing of TET2, ASXL1, EZH2, DNMT3A, and IDH1/2 revealed that patients failing to achieve CMR had a higher frequency of mutations outside the Janus kinase-signal transducer and activator of transcription pathway and were more likely to acquire new mutations during therapy. Patients with both JAK2V617F and TET2 mutations at therapy onset had a higher JAK2V617F mutant allele burden and a less significant reduction in JAK2V617F allele burden compared with JAK2 mutant/TET2 wild-type patients. These data demonstrate that PEG-IFN-α-2a induces sustained CMR in a subset of PV or ET patients, and that genotypic context may influence clinical and molecular response to PEG-IFN-α-2a.

[Detection of serum neopterin in patients with hemophagocytic lymphohistiocytosis and its significance].

This study was aimed to detect the peripheral blood serum neopterin (Npt) level in the patients with hemophagocytic lymphohistiocytosis (HLH) and to explore its significance in HLH. The enzyme-linked immunosorbent assay (ELISA) was applied to detect the serum Npt level and sCD25 level in 20 HLH patients before and after treatment and 15 healthy controls. The results indicated that the serum Npt and sCD25 levels in HLH patients were significantly higher than those in healthy controls (P < 0.0001). The serum Npt and sCD25 levels in the HLH group decreased significantly after treatment, respectively (P < 0.0001). The correlation analysis of Npt with sCD25 before and after treatment showed that they had significant correlation (r = 0.81, P < 0.05 before treatment; r = 0.65, P < 0.05 after treatment). Meanwhile, the level of serum Npt and ferritin had a significant correlation in newly diagnosed HLH patients (r = 0.55, P < 0.05). It is concluded that the serum Npt may play an important role in the HLH pathogenesis, the enhancement of Npt levels has an important significance for diagnosis and evaluation for HLH.

Mutational analysis of therapy-related myelodysplastic syndromes and acute myelogenous leukemia.

Therapy-related myelodysplastic syndromes and acute myelogenous leukemia comprise a poor-risk subset of myelodysplastic syndromes and acute myelogenous leukemia. Large-scale mutation profiling efforts in de novo myelodysplastic syndromes have identified mutations that correlate with clinical features, but such mutations have not been investigated in therapy-related myelodysplastic syndromes and acute myelogenous leukemia. Genomic DNA from 38 patient samples were subjected to high throughput polymerase chain reaction and sequenced for TP53, TET2, DNMT3A, ASXL1, IDH1, IDH2, EZH2, EED, SUZ12, RBBP4, SRSF2, U2AF35, and SF3B1. We identified somatic mutations in 16 of 38 (42%) patients. TP53 mutations were the most common lesion, detected in 8 of 38 (21%) patients, followed by TET2 in 4 of 38 (10.5%). Cases with a TP53 mutation or loss of the TP53 locus had a worse overall survival compared to those with wild-type TP53 (8.8 vs. 37.4 months; P=0.0035).

[Detection and clinical features of MLL gene rearrangement in adult patients with acute leukemia].

This study was purposed to investigate the incidence of mixed lineage leukemia (MLL) gene rearrangement and partner gene types as well as the clinical features and prognosis of acute leukemia (AL) with this rearrangement through detection in adult AL using combination of 3 techniques, and to evaluate the clinical value of this combination detection. The MLL gene rearrangement in 183 cases of adult AL was detected by combination of conventional cytogenetics, split signal FISH and multiplex nested PCR. The results showed that the incidence of MLL rearrangements in adult patients with AL was low (8.2%), and MLL-AF4 fusion gene was most common and predominant in acute lymphoblastic leukemia (ALL), while the MLL-AF6 and MLL-AF9 were most frequent in acute myeloid leukemia (AML). Extramedullary involvements were found in 40% of MLL-rearranged AL patients, and 33.3% of patients with MLL-rearranged AL reached to complete remission within 30 days during induction chemotherapy. In addition, in this cohort of MLL-rearranged adult AL patients, the 3-month relapse rate and 6-month overall survival rate were 50.0% and 50.0% respectively. It is concluded that the rate of missed diagnosis of CC technique for patients with MLL-rearranged AL reached to 60% in this study, while the combination of CC, FISH and multiplex nested PCR has been confirmed to have important significance for evaluating prognosis and conducting clinical therapy of patients with MLL-rearranged AL.

The significance of 18F-FDG PET/CT in secondary hemophagocytic lymphohistiocytosis.

This study was aimed to investigate the significance of 18F-FDG PET/CT in secondary hemophagocytic lymphohistiocytosis (sHLH) patients. A total of 18 patients received 18F-FDG PET/CT scan at initial diagnosis. All patients (18/18) had at least 3 organs involved, with increased FDG metabolism in different degrees. Fifteen cases (15/18) had definite underlying diseases, including infections (IAHLH), rheumatosis (RAHLH), or malignancy (MAHLH). The SUVmax of patients in MAHLH group was significantly higher than patients in IAHLH group or RAHLH group (P = 0.015, P = 0.045). Furthermore, the SUVmax of patients in IAHLH group was significantly higher than patients of RAHLH group (P = 0.043). Therefore, we concluded that 18F-FDG PET/CT may especially play important role in differential diagnosis of sHLH.

Genetic analysis of patients with leukemic transformation of myeloproliferative neoplasms shows recurrent SRSF2 mutations that are associated with adverse outcome.

Leukemic transformation (LT) of myeloproliferative neoplasms (MPNs) is associated with a poor prognosis and resistance to therapy. Although previous candidate genetic studies have identified mutations in MPN patients who develop acute leukemia, the complement of genetic abnormalities in MPN patients who undergo LT is not known nor have specific molecular abnormalities been shown to have clinical relevance in this setting. We performed high-throughput resequencing of 22 genes in 53 patients with LT after MPN to characterize the frequency of known myeloid mutations in this entity. In addition to JAK2 and TET2 mutations, which occur commonly in LT after MPN, we identified recurrent mutations in the serine/arginine-rich splicing factor 2 (SRSF2) gene (18.9%) in acute myeloid leukemia (AML) transformed from MPNs. SRSF2 mutations are more common in AML derived from MPNs compared with LT after myelodysplasia (4.8%) or de novo AML (5.6%), respectively (P=.05). Importantly, SRSF2 mutations are associated with worsened overall survival in MPN patients who undergo LT in univariate (P=.03; HR, 2.77; 95% CI, 1.10-7.00) and multivariate analysis (P<.05; HR, 2.11; 95% CI, 1.01-4.42). These data suggest that SRSF2 mutations contribute to the pathogenesis of LT and may guide novel therapeutic approaches for MPN patients who undergo LT.