Gilteritinib-based combination therapy in adult relapsed/refractory FLT3-mutated acute myeloid leukaemia.

Gilteritinib, a potent FMS-like tyrosine kinase 3 (FLT3) inhibitor, was approved for relapsed/refractory (R/R) FLT3-mutated acute myeloid leukaemia (AML) patients but still showed limited efficacy. Here, we retrospectively analysed the efficacy and safety of different gilteritinib-based combination therapies (gilteritinib plus hypomethylating agent and venetoclax, G + HMA + VEN; gilteritinib plus HMA, G + HMA; gilteritinib plus venetoclax, G + VEN) in 33 R/R FLT3-mutated AML patients. The composite complete response (CRc) and modified CRc (mCRc) rates were 66.7% (12/18) and 88.9% (16/18) in patients received G + HMA + VEN, which was higher compared with that in G + HMA (CRc: 18.2%, 2/11; mCRc: 45.5%, 5/11) or G + VEN (CRc: 50.0%, 2/4; mCRc: 50.0%, 2/4). The median overall survival (OS) for G + HMA + VEN, G + HMA and G + VEN treatment was not reached, 160.0 days and 231.0 days. The median duration of remission (DOR) for G + HMA + VEN, G + HMA and G + VEN treatment was not reached, 82.0 days and 77.0 days. Four patients in the G + HMA + VEN group received alloHSCT after remission exhibited prolonged median DOR. The most common grade 3/4 adverse events were cytopenia, febrile neutropenia and pulmonary infection; there were no differences among the three groups. In conclusion, our data demonstrated promising response of G + HMA + VEN combination therapy in R/R FLT3-mutated AML, and it may be considered an effective therapy bridge to transplantation.

Venetoclax plus daunorubicin and cytarabine in newly diagnosed acute myeloid leukemia patients: A propensity score-matched analysis.

Venetoclax plus 3 + 7 daunorubicin and cytarabine chemotherapy (DAV) has shown safety and efficacy in eligible patients with newly diagnosed acute myeloid leukemia (AML). However, there are no direct comparisons between DAV and 3 + 7 daunorubicin and cytarabine chemotherapy (DA) alone. We performed a propensity score-matched analysis to compare the outcomes of DAV group with historical DA group and identify the clinical and molecular characteristics of patients who might benefit from the DAV regimen. The DAV group had a higher Complete remission (CR) rate than the DA group (90% vs. 55%, p = 0.008). 25 (96%) patients in the DAV group had a higher MRD-negative CRc rate compared with 13 (62%) patients in the DA group (p = 0.006). After a median follow-up duration of 19.15 (IQR 17.13-21.67) months, the DAV group had an improved overall survival (p = 0.001) and event-free survival (p = 0.069), but not disease-free survival (p = 0.136). Collectively, DAV regimen induced high CR rates and deep MRD-negative CRc rates after one cycle of induction therapy, as well as prolonged the overall survival, in young adult patients with AML who were eligible for intensive chemotherapy. The addition of venetoclax to intensive chemotherapy should be considered in the future to achieve better survival advantages in eligible AML patients.

New insights into the clinical characteristics of SETD2-mutated acute myeloid leukaemia.

As reported, SETD2 is recurrently mutated in acute myeloid leukaemia (AML), but knowledge about the specifics is limited. We enrolled 530 consecutive newly diagnosed AML patients in our study, and we analysed the distribution pattern and prognostic role of SETD2 mutation in AML. SETD2 mutation was found to affect 6.3% of AML patients, and it frequently co-occurred with IDH2, NRAS and CEBPA mutations. SETD2-mutated patients saw excellent therapeutic responses but failed to gain better survival time than other patients. This could be because of the high recurrence and mortality in SETD2-mutated patients who have additional mutations, such as NRAS mutation.

Dasatinib plus prednisone as induction and consolidation for adults with Ph-positive acute lymphoblastic leukaemia: A single-arm, multicentre, phase 2 trial.

To reducing chemotherapy-related toxicity, the chemo-free regimens become a new trend of Ph + ALL treatment. Therefore, we conducted a phase 2 trial of dasatinib plus prednisone, as induction (Course I) and early consolidation (Courses II and III) treating newly diagnosed Ph + ALL. The trial was registered at www.chictr.org.cn, ChiCTR2000038053. Forty-one patients were enrolled from 15 hospitals. The complete remission (CR) was 95% (39/41), including two elderly induction deaths. By the end of Course III, 25.6% (10/39) of patients achieved a complete molecular response. With a median follow-up of 15.4 months, 2-year disease-free survival (DFS) were 100% and 33% for patients who receiving haematopoietic stem cell transplantation (HSCT) at CR1 and receiving chemotherapy alone respectively. When censored at time of HSCT, 2-year DFS were 51% and 45% for young and elderly patients (p = 0.987). 2-year overall survival were 45%, 86% and 100% for patients without HSCT, receiving HSCT after relapse and receiving HSCT at CR1 respectively. A total of 12 patients had marrow recurrences and one had CNS relapse, with 38% occurred early (between Courses I and III). IKZF1 gene deletion was shown to be associated with relapse (p = 0.019). This chemo-free induction and early consolidation regimen was efficacious and well-tolerated in de novo Ph + ALL. Allogeneic HSCT conferred definite survival advantage after chemo-free induction.

Trimethoprim-sulfamethoxazole prevents interstitial pneumonitis in B-cell lymphoma patients receiving chemotherapy: a propensity score matching analysis.

B-cell lymphoma is the most prevalent type of non-Hodgkin lymphoma, for which the standard treatment regimen includes rituximab combined with CHOP. However, some patients may develop interstitial pneumonitis (IP), which can be caused by various factors; one of the most important factors is Pneumocystis jirovecii. It is crucial to investigate the pathophysiology of IP and implement preventive measures since IP can be fatal for some people. The data were collected from the First Affiliated Hospital, Zhejiang University School of Medicine, where patients with B-cell lymphoma received the R-CHOP/R-CDOP regimen with or without prophylactic use of trimethoprim-sulfamethoxazole (TMP-SMX). Multivariable logistic regression and propensity score matching (PSM) were used to investigate any potential association. Eight hundred thirty-one patients with B-cell lymphoma were classified into two groups: the non-prophylaxis group without TMP-SMX (n=699) and the prophylaxis group with TMP-SMX (n = 132). IP occurred in 66 patients (9.4%, all in the non-prophylaxis group), with an onset median of three cycles of chemotherapy. Multiple logistic regression analysis demonstrated that IP incidence was associated with pegylated liposome doxorubicin (OR=3.29, 95% CI 1.84-5.90, P<0.001). After utilizing a 1:1 matching algorithm for PSM, 90 patients from each group were obtained. There was a statistical difference between the two cohorts in the IP incidence (non-prophylaxis 12.2% vs prophylaxis 0.0%, P <0.001). The prophylactic use of TMP-SMX could prevent the occurrence of IP whose risk factor was pegylated liposome doxorubicin after chemotherapy for B-cell lymphoma.

Epigenetic priming with decitabine followed by low dose idarubicin and cytarabine in acute myeloid leukemia evolving from myelodysplastic syndromes and higher-risk myelodysplastic syndromes: a prospective multicenter single-arm trial.

Patients with acute myeloid leukemia (AML) evolving from myelodysplastic syndrome (MDS) or higher-risk MDS have limited treatment options and poor prognosis. Our previous single-center study of decitabine followed by low dose idarubicin and cytarabine (D-IA) in patients with myeloid neoplasms showed promising primary results. We therefore conducted a multicenter study of D-IA regimen in AML evolving from MDS and higher-risk MDS. Patients with AML evolving from MDS or refractory anemia with excess blasts type 2 (RAEB-2) (based on the 2008 WHO classification) were included. The D-IA regimen (decitabine, 20 mg/m2 daily, days 1 to 3; idarubicin, 6 mg/m2 daily, days 4 to 6; cytarabine 25 mg/m2 every 12 hours, days 4 to 8; granulocyte colony stimulating factor [G-CSF], 5 µg/kg, from day 4 until neutrophil count increased to 1.0 × 109 /L) was administered as induction chemotherapy. Seventy-one patients were enrolled and treated, among whom 44 (62.0%) had AML evolving from MDS and 27 (38.0%) had RAEB-2. Twenty-eight (63.6%) AML patients achieved complete remission (CR) or complete remission with incomplete blood count recovery (CRi): 14 (31.8%) patients had CR and 14 (31.8%) had CRi. Six (22.2%) MDS patients had CR and 15 (55.6%) had marrow complete remission. The median overall survival (OS) was 22.4 months for the entire group, with a median OS of 24.2 months for AML and 20.0 months for MDS subgroup. No early death occurred. In conclusion, the D-IA regimen was effective and well tolerated, representing an alternative option for patients with AML evolving from MDS or MDS subtype RAEB-2.

Decitabine improves overall survival in myelodysplastic syndromes-RAEB patients aged ≥60 years and has lower toxicities: Comparison with low-dose chemotherapy.

Decitabine and low-dose chemotherapy are common treatments for intermediate and high risk myelodysplastic syndromes (MDS). In this study, we retrospectively assessed the efficacy and toxicity of the two regimens for MDS-refractory anemia with excess blasts (MDS-RAEB) patients. A total of 112 patients with a diagnosis of MDS-RAEB are included. The overall response (OR) and complete remission (CR) rate was comparable between the two groups (OR: 64.1% vs. 66.7%, p = 0.60; CR: 23.4% vs. 31.3%, p = 0.64). The OR rates of 20 mg/m2/day and 15 mg/m2/day decitabine regimen were comparable (69.0% vs. 60.0%, p = 0.46). Overall survival (OS) did not differ significantly between the groups (20.7 vs. 13.5 months, p = 0.17). In a subgroup analysis that included only patients at ≥60 years of age, survival benefit of decitabine was apparent (20.6 vs. 10.0 months, p = 0.03). In hematological toxicities, the lowest count of platelet in the decitabine group was higher significantly. And, the incidence of Grade 3-4 infection in the decitabine group was lower significantly. Our results demonstrate that both decitabine and low-dose chemotherapy are effective for MDS-RAEB, but decitabine was safer. Decitabine might be a better choice for patients at ≥60 years of age.

Clinical Significance of Prognostic Nutritional Index for Patients with Diffuse Large B-cell Lymphoma.

To analyze the clinical characteristics and prognostic value of prognostic nutritional index (PNI) for diffuse large B-cell lymphoma (DLBCL) treated in the rituximab era, baseline clinical and disease characteristics were recorded in our hospital. Concentration of T-helper cell type (Th1/Th2/Th17) cytokine profiles were measured by flow cytometry. DLBCL patients were classified into low and high PNI group based on the cutoff value as previously reported. Clinical features and survivals were compared between high and low group. In all, 114 (37%) out of 309 patients were classified as low PNI group. The low group had lower levels of albumin, hemoglobin and lymphocyte counts, and older age, and high lactate dehydroxygenase (LDH), and high frequencies of advanced stage, poor performance status, B symptoms, extranodal involvement, and higher level of interferon gamma (INF-γ). Low PNI was associated with poor overall survival (OS) in univariate analyses. But these significances did not stand in the paired patients matched by the well-established prognostic factors. In parallel, there was no significance between survival and PNI in the multivariate analyses. PNI was closely correlated with the well-established prognostic factors for DLBCL patients and was not an independent prognostic factor in our study.

[Bortezomib-induced peripheral neuropathy in multiple myeloma patients].

OBJECTIVE: To describe the side effects of bortezomib in treatment of multiple myeloma (MM), especially the incidence of peripheral neuropathy (PN). METHODS: Information of 107 patients with MM who were treated with bortezomib in the First Affiliated Hospital of Zhejiang University from 2009 to 2014, were collected and analyzed retrospectively, to analyze the occurrence of adverse events during the treatment, especially the incidences of PN in each cycle and in different patients. RESULTS: A total of 40 (37%) patients suffered from PN, among which 13 patients were grade 3 PN and no patients reported grade 4 PN. Other common treatment-related side effects were thrombocytopenia, gastrointestinal reactions, fatigue, lung infection, herpes zoster in turn. In 44 MM patients treated strictly with bortezomib 1.3 mg/m(2) (days 1, 4, 8, 11) of each 3-week cycle, 20(45%) patients suffered from PN, of which 6 (14%) patients got grade 3 PN. In other 63 patients who received bortezomib less than 1.3 mg/m(2), 20 (32%) patients got PN and 7(11%) patients were grade 3 PN. There was no significant difference in the incidence of PN between the two groups of MM patients mentioned above (P=0.149), as well as the incidence of grade 3 PN (P=0.694). Univariate and multivariate analyse revealed that gender, age, a history of hypertensive disease, diabetes or hepatitis B virus infection, baseline PN symptoms and a history of neurotoxicity drug therapy were all not risk factors for PN (all P>0.05). CONCLUSIONS: The reduction of bortezomib do not decrease the incidence of PN in bortezomib treatment of MM. Age, a history of diabetes and baseline PN symptoms are not risk factors for PN in bortezomib treatment of MM.

Venetoclax plus cytarabine and azacitidine in relapsed/refractory AML: An open-label, single-arm, phase 2 study.

BACKGROUND: The outcome of relapsed/refractory (R/R) acute myeloid leukemia (AML) remains extremely poor. Venetoclax (VEN)-based regimens have shown promise in treating R/R AML. OBJECTIVE: This phase 2 study aimed to systematically evaluate the efficacy and safety of the VAA regimen (VEN plus Cytarabine and Azacitidine) in R/R AML patients. METHODS: Thirty R/R AML patients were enrolled. The study adopted a stepwise ramp-up of VEN dosing, starting with 100 mg on day 1, escalating to 200 mg on day 2, and reaching 400 mg from day 3 to day 9. Cytarabine (10 mg/m2, q12h) was administered intravenously twice daily from days 1 to 10, and Azacitidine (75 mg/m2) was administered via subcutaneous injection once daily from days 1-7. The primary efficacy endpoint was the composite complete remission rate (CRc), including complete response (CR) and complete response with incomplete blood count recovery (CRi). Secondary endpoints included overall survival (OS), duration of response (DOR), and safety analysis. RESULTS: The CRc rate was 63.3% (19/30), with CR in 36.7% of patients and CRi in 26.7%. Notably, 14 (73.7%) of 19 patients achieving CRc showed undetectable measurable residual disease by flow cytometry. With a median follow-up of 10.7 months, the median OS had not been reached, and the median DOR was 18.3 months. The most common grade 3-4 adverse events (AEs) were neutropenia (100%), anemia (96.7%), thrombocytopenia (90.0%), and leukopenia (90.0%). Infections, with pneumonia being the most prevalent (43.3%), were observed, including one fatal case of Pseudomonas aeruginosa septicemia. There were no treatment-related deaths. CONCLUSION: The VAA regimen is an effective and safe option for patients with R/R AML, demonstrating a high CRc rate and manageable safety profile.

[Relationship between clinical characteristics and myelodysplastic syndrome patients with isocitrate dehydrogenase gene mutations].

OBJECTIVE: To assess the prevalence and clinical characteristics of isocitrate dehydrogenase 1 and 2 (IDH 1 and IDH2) gene mutations in myelodysplastic syndrome (MDS) patients. METHODS: Pretreatment bone marrow specimens were enriched for mononuclear cells in 108 adult patients with de novo MDS from January 2006 to August 2012. Genomic DNA was extracted from mononuclear cells. And PCR and direct sequencing were performed to sequence exon 4 of IDH gene. RESULTS: IDH mutations were discovered in 11 MDS patients (10.19%, 11/108) and all were heterozygous. The frequencies of IDH1 and IDH2 mutations were 5.56% (6/108) and 4.63% (5/108) respectively. Only one type of IDH1 mutation (c.394C→, p.R132C) was identified in our cohort. All IDH2 mutations caused the changes of R140 (c.419G→A, p.R140Q). However IDH2 R172 mutation was not detected. The combined mutations of IDH1 and IDH2 were not simultaneously observed in the same patient. The prevalence of IDH mutation was higher in advanced-stage MDS than those early-stage MDS patients. Mutated and wild-type groups had significantly difference in bone marrow blast percentage (median 12.5% vs 6.0%, P = 0.013) at diagnosis, but not in white blood cell count, hemoglobin level and platelet count, etc. In the normal karyotype group, the frequencies of IDH mutations were as similar as those in the abnormal karyotype group (10.61% (7/66) vs 10.00% (4/40), P > 0.05). The median follow-up time was 472 d, our data indicated that IDH mutations were correlated with poor overall survival (median time 512 vs 740 d, P = 0.017). IDH mutations were also an inferiorly predictive factor in the intermediate-1 group patients of International Prognostic Scoring System (IPSS) (median survival time 512 d vs not reached, P = 0.038). There was also better efficacies than other treatments in IDH mutation positive patients (median survival time 623 vs 165 d, P = 0.049). CONCLUSIONS: IDH mutation is a vital biomarker for better risk stratification of MDS patients with and improving IPSS. Hypomethylation agents may be effective for treating IDH mutation positive patients.

A hybrid energy-based and AI-based screening approach for the discovery of novel inhibitors of JAK3.

The JAKs protein family is composed of four isoforms, and JAK3 has been regarded as a druggable target for the development of drugs to treat various diseases, including hematologic tumors, cancer, and neuronal death. Therefore, the discovery of JAK3 inhibitors with novel scaffolds possesses the potential to provide additional options for drug development. This article presents a structure-based hybrid high-throughput virtual screening (HTVS) protocol as well as the DeepDock algorithm, which is based on geometric deep learning. These techniques were used to identify inhibitors of JAK3 with a novel sketch from a specific "In-house" database. Using molecular docking with varying precision, MM/GBSA, geometric deep learning scoring, and manual selection, 10 compounds were obtained for subsequent biological evaluation. One of these 10 compounds, compound 8, was found to have inhibitory potency against JAK3 and the MOLM-16 cell line, providing a valuable lead compound for further development of JAK3 inhibitors. To gain a better understanding of the interaction between compound 8 and JAK3, molecular dynamics (MD) simulations were conducted to provide more details on the binding conformation of compound 8 with JAK3 to guide the subsequent structure optimization. In this article, we achieved compound 8 with a novel sketch possessing inhibitory bioactivity against JAK3, and it would provide an acceptable "hit" for further structure optimization and modification to develop JAK3 inhibitors.

Dyslipidemia in diffuse large B-cell lymphoma based on the genetic subtypes: a single-center study of 259 Chinese patients.

Background: Diffuse large B-cell lymphoma (DLBCL) is a kind of highly heterogeneous non-Hodgkin lymphoma, both in clinical and genetic terms. DLBCL is admittedly categorized into six subtypes by genetics, which contain MCD, BN2, EZB, N1, ST2, and A53. Dyslipidemia is relevant to a multitude of solid tumors and has recently been reported to be associated with hematologic malignancies. We aim to present a retrospective study investigating dyslipidemia in DLBCL based on the molecular subtypes. Results: This study concluded that 259 patients with newly diagnosed DLBCL and their biopsy specimens were available for molecular typing. Results show that the incidence of dyslipidemia (87.0%, p <0.001) is higher in the EZB subtype than in others, especially hypertriglyceridemia (78.3%, p = 0.001) in the EZB subtype. Based on the pathological gene-sequencing, patients with BCL2 gene fusion mutation are significantly correlative with hyperlipidemia (76.5%, p = 0.006) and hypertriglyceridemia (88.2%, p = 0.002). Nevertheless, the occurrence of dyslipidemia has no remarkable influence on prognosis. Conclusion: In summary, dyslipidemia correlates with genetic heterogeneity in DLBCL without having a significant influence on survival. This research first connects lipids and genetic subtypes in DLBCL.

Repressing HIF-1α-induced HDAC9 contributes to the synergistic effect of venetoclax and MENIN inhibitor in KMT2Ar AML.

KMT2A-rearranged acute myeloid leukemia (KMT2Ar-AML) is an aggressive subtype of AML with poor response and prognosis. KMT2Ar-AML has been demonstrated to be sensitive to BCL2 inhibitor venetoclax (VEN), but these patients are unable to benefit from current VEN-based regimen (VEN plus azacitidine or low dose-cytarabine), so a novel and KMT2A rearrangement-specific targeting partner is required, and MENIN inhibitor (MEN1i) is a promising one. Herein, we investigated the effect and mechanism of VEN plus MEN1i in KMT2Ar-AML. Our results showed that VEN and MEN1i exhibited a striking synergistic effect in KMT2Ar-AML cell lines (in vitro), primary KMT2Ar-AML cells (ex vivo), and MOLM13 xenotransplantation model (in vivo). Furthermore, we found that VEN plus MEN1i significantly enhanced apoptotic induction in KMT2Ar-AML cell lines. VEN or MEN1i monotherapy disrupted balance of BCL-2/BCL-XL or down-regulated HOXA9/MEIS1, respectively, but these mechanisms were not further strengthened by their combination. RNA-Sequencing identified that HDAC9 was specifically repressed by VEN plus MEN1i rather than monotherapy. We demonstrated that HDAC9 was indispensable for KMT2Ar-AML proliferation and its repression contributed to proliferation inhibition of VEN plus MEN1i. Moreover, we found that hypoxia induced HDAC9 expression in KMT2Ar-AML, and VEN plus MEN1i inhibited hypoxia pathway, especially HIF-1A, and its target HDAC9. As our results indicated, VEN plus MEN1i-mediated HDAC9 down-regulation was partially dependent on HIF-1A repression in KMT2Ar-AML. Hypoxia induction sensitized KMT2Ar-AML to VEN plus MI-503-mediated proliferation inhibition and apoptosis induction. Therefore, repressing HIF-1A-induced HDAC9 contributed to the synergistic effect of VEN and MEN1i in KMT2Ar-AML.

The clinical impact of IKZF1 mutation in acute myeloid leukemia.

Genetic heterogeneity poses a great challenge to the understanding and management of acute myeloid leukemia (AML). Knowledge of the IKZF1 mutation in AML specifically is extremely limited. In a previous work, we described the distribution pattern of IKZF1 mutation in AML, but its clinical impact has remained undefined due to the limited number of cases. Herein, we attempt to answer this question in one relatively large cohort covering 522 newly diagnosed AML patients. A total of 26 IKZF1 mutations were found in 20 AML patients (20/522, 3.83%). This condition has a young median age of onset of morbidity (P = 0.032). The baseline characteristics of IKZF1-mutated and wild-type patients were comparable. IKZF1 mutation showed significant co-occurrences with CEBPA (P < 0.001), SF3B1 (P < 0.001), and CSF3R (P = 0.005) mutations, and it was mutually exclusive with NPM1 mutation (P = 0.033). Although IKZF1-mutated AML was more preferably classified into the intermediate-risk group (P = 0.004), it showed one inferior complete remission rate (P = 0.032). AML with high burden of IKZF1 mutation (variant allele frequency > 0.20) showed relatively short overall survival period (P = 0.012), and it was an independent factor for the increased risk of death (hazard ratio, 6.101; 95% CI 2.278-16.335; P = 0.0003). In subgroup analysis, our results showed that IKZF1 mutation conferred poor therapeutic response and prognosis for SF3B1-mutated AML (P = 0.0017). We believe this work improves our knowledge of IKZF1 mutation.

Etoposide, dexamethasone, and pegaspargase with sandwiched radiotherapy in early-stage natural killer/T-cell lymphoma: A randomized phase III study.

Methotrexate, etoposide, dexamethasone, and pegaspargase (MESA) with sandwiched radiotherapy is known to be effective for early-stage extranodal natural killer/T-cell lymphoma, nasal type (NKTCL). We explored the efficacy and safety of reduced-intensity, non-intravenous etoposide, dexamethasone, and pegaspargase (ESA) with sandwiched radiotherapy. This multicenter, randomized, phase III trial enrolled patients aged between 14 and 70 years with newly diagnosed early-stage nasal NKTCL from 27 centers in China. Patients were randomly assigned (1:1) to receive ESA (pegaspargase 2,500 IU/m2 intramuscularly on day 1, etoposide 200 mg orally, and dexamethasone 40 mg orally on days 2-4) or MESA (methotrexate 1 g/m2 intravenously on day 1, etoposide 200 mg orally, and dexamethasone 40 mg orally on days 2-4, and pegaspargase 2,500 IU/m2 intramuscularly on day 5) regimen (four cycles), combined with sandwiched radiotherapy. The primary endpoint was overall response rate (ORR). The non-inferiority margin was -10.0%. From March 16, 2016, to July 17, 2020, 256 patients underwent randomization, and 248 (ESA [n = 125] or MESA [n = 123]) made up the modified intention-to-treat population. The ORR was 88.8% (95% confidence interval [CI], 81.9-93.7) for ESA with sandwiched radiotherapy and 86.2% (95% CI, 78.8-91.7) for MESA with sandwiched radiotherapy, with an absolute rate difference of 2.6% (95% CI, -5.6-10.9), meeting the non-inferiority criteria. Per-protocol and sensitivity analysis supported this result. Adverse events of grade 3 or higher occurred in 42 (33.6%) patients in the ESA arm and 81 (65.9%) in the MESA arm. ESA with sandwiched radiotherapy is an effective, low toxicity, non-intravenous regimen with an outpatient design, and can be considered as a first-line treatment option in newly diagnosed early-stage nasal NKTCL.

Prognostic effects of clinical parameters, genetic abnormalities, and subtypes in primary gastric diffuse large B-cell lymphoma: a cohort analysis of 146 patients.

This study included 146 primary gastric diffuse large B-cell lymphoma patients. Next-generation RNA sequencing and fluorescent in situ hybridization were performed on tumors from 27 and 38 patients, respectively. Five-year and 10-year overall survival (OS) rates were 77% and 57%, respectively. Lugano and TNM clinical stage were independent survival factors. Tier I mutation was found in 21 patients. The genetic subtypes were A53 (n = 3), MCD (n = 5), BN2 (n = 5), N1 (n = 5), EZB (n = 1), and NOS (n = 8). OS was significantly shorter in high-risk genetic subtypes (A53, MCD, and N1) than low-risk subtypes (BN2, EZB, and NOS). Frequencies of high-risk genetic subtypes were higher in patients with Lugano stage II/IV and TNM clinical stage III + IV than in those with Lugano stage I and TNM clinical stage I + II. Although genetic testing was performed in only a small number of cases, the results suggested that high-risk genetic subtypes were associated with advanced clinical stages and shorter survival.

Rituximab, lenalidomide and BTK inhibitor as frontline treatment for elderly or unfit patients with diffuse large B-cell lymphoma: a real-world analysis of single center.

The combination of rituximab, lenalidomide, and Bruton's tyrosine kinase inhibitor (BTKi) ibrutinib, followed by chemotherapy, has shown high efficacy in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) in Smart Start trial. We aimed to evaluate the efficacy, safety of SMART (rituximab + lenalidomide + BTKi) regimen and SMART-START regimen as a first-line treatment in elderly or unfit DLBCL patients. 31 patients were included, 17 used SMART regimen, with median age 82 years, 14 unfit patients received SMART-START regimen. 14/16 (87.5%) patients in SMART group achieved overall response (OR), with 10/16 (62.5%) achieved complete response (CR). 12/13 (92.3%) patients in SMART-START group achieved OR, with 8/13 (61.5%) achieved CR. With a median follow-up of 15.4 (3-29.1) months, median progression-free survival (PFS) and overall survival (OS) have not been reached, 1-year PFS was 81% in SMART group and 84% in SMART-START group. Common grade 3-4 adverse events (AEs) during SMART regimen were neutropenia (8 [25.8%]), infection (6 [19.4%]) and skin rash (3 [9.7%]). Our study shows that SMART regimen is an effective and safe therapy for elderly DLBCL patients, and SMART-START regimen can be used in unfit patients who could not tolerate intensive chemotherapy in the onset.

Venetoclax plus 3 + 7 daunorubicin and cytarabine chemotherapy as first-line treatment for adults with acute myeloid leukaemia: a multicentre, single-arm, phase 2 trial.

BACKGROUND: Adults with acute myeloid leukaemia have unsatisfactory clinical outcomes and rates of complete remission. Venetoclax combined with azacytidine or low-dose cytarabine has shown efficacy in adults aged 75 years or older (or 18-74 years with comorbidities precluding intensive chemotherapy) with acute myeloid leukaemia. We aimed to investigate the activity and safety of venetoclax plus 3+7 daunorubicin and cytarabine chemotherapy in adults with acute myeloid leukaemia. METHODS: We conducted a two-stage, single-arm, phase 2 trial at three public hospitals in China. We enrolled patients aged 18-60 years with previously untreated de novo acute myeloid leukaemia and an Eastern Cooperative Oncology Group performance status of 0-2. Patients received induction treatment with intravenous daunorubicin (60 mg/m2 on days 1-3), intravenous cytarabine (100 mg/m2 on days 1-7), and oral venetoclax (100 mg on day 4, 200 mg on day 5, and 400 mg on days 6-11; DAV regimen). For induction therapy, the length of the treatment was 28-35 days per cycle and the number of treatment cycles was one or two. The primary endpoint was the composite complete remission rate (complete remission plus complete remission with incomplete blood cell count recovery) after one cycle of induction treatment, assessed in the as-treated population. Secondary endpoints were bone marrow measurable residual disease by flow cytometry, event-free survival, overall survival, and adverse events. This trial is ongoing and is registered with Chinese Clinical Trial Registry, ChiCTR2000041509. FINDINGS: Between Dec 25, 2020, and July 7, 2021, 36 patients were assessed for eligibility and 33 were enrolled. 15 (45%) patients were men and 18 (55%) were women, and all were Asian. The composite complete remission rate after one cycle of DAV regimen was 91% (95% CI 76-98; 30 of 33 patients) in the entire cohort. 29 (97%) of 30 patients who reached complete remission had undetectable measurable residual disease (ie, <0·1%). Grade 3 or worse adverse events included neutropenia in 33 (100%) of 33 patients, thrombocytopenia in 33 (100%), anaemia in 33 (100%), febrile neutropenia in 18 (55%), pneumonia in seven (21%), and sepsis in four (12%). No treatment-related deaths occurred. With a median follow-up of 11 months (IQR 9-12), estimated 1-year overall survival was 97% (95% CI 91-100) and 1-year event-free survival was 72% (56-94). INTERPRETATION: The DAV regimen represents an effective induction therapy for newly diagnosed adults with acute myeloid leukaemia, which resulted in a high rate of complete remission. These findings are an important contribution to the field, showing a safe strategy to incorporate venetoclax into the most common induction regimen used to treat newly diagnosed acute myeloid leukaemia internationally. FUNDING: Leading Innovative and Entrepreneur Team Introduction Program of Zhejiang, National Natural Science Foundation of China, Key Research and Development Program of Zhejiang. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Oral arsenic and retinoic acid for high-risk acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) has become curable over 95% patients under a complete chemo-free treatment with all-trans retinoic acid (ATRA) and arsenic trioxide in low-risk patients. Minimizing chemotherapy has proven feasible in high-risk patients. We evaluated oral arsenic and ATRA without chemotherapy as an outpatient consolidation therapy and no maintenance for high-risk APL. We conducted a multicenter, single-arm, phase 2 study with consolidation phases. The consolidation therapy included Realgar-Indigo naturalis formula (60 mg/kg daily in an oral divided dose) in a 4-week-on and 4-week-off regimen for 4 cycles and ATRA (25 mg/m2 daily in an oral divided dose) in a 2-week-on and 2-week-off regimen for 7 cycles. The primary end point was the disease-free survival (DFS). Secondary end points included measurable resident disease, overall survival (OS), and safety. A total of 54 participants were enrolled at seven centers from May 2019. The median age was 40 years. At the median follow-up of 13.8 months (through April 2022), estimated 2-year DFS and OS were 94% and 100% in an intention-to-treat analysis. All the patients achieved complete molecular remission at the end of consolidation phase. Two patients relapsed after consolidation with a cumulative incidence of relapse of 6.2%. The majority of adverse events were grade 1-2, and only three grade 3 adverse events were observed. Oral arsenic plus ATRA without chemotherapy was active as a first-line consolidation therapy for high-risk APL.Trial registration: chictr.org.cn number, ChiCTR1900023309.