Initial Efficacy of the COVID-19 mRNA Vaccine Booster and Subsequent Breakthrough Omicron Variant Infection in Patients with B-Cell Non-Hodgkin's Lymphoma: A Single-Center Cohort Study.

It has been suggested that the effect of coronavirus disease 2019 (COVID-19) booster vaccination in patients with B-cell non-Hodgkin's lymphoma (B-NHL) is inferior to that in healthy individuals. However, differences according to histological subtype or treatment status are unclear. In addition, there has been less research on patients who subsequently develop breakthrough infections. We investigated the effects of the first COVID-19 booster vaccination for patients with B-NHL and the clinical features of breakthrough infections in the Omicron variant era. In this study, B-NHL was classified into two histological subtypes: aggressive lymphoma and indolent lymphoma. Next, patients were subdivided according to treatment with anticancer drugs at the start of the first vaccination. We also examined the clinical characteristics and outcomes of patients who had breakthrough infections after a booster vaccination. The booster effect of the COVID-19 mRNA vaccine in patients with B-NHL varied considerably depending on treatment status at the initial vaccination. In the patient group at more than 1 year after the last anticancer drug treatment, regardless of the histological subtype, the booster effect was comparable to that in the healthy control group. In contrast, the booster effect was significantly poorer in the other patient groups. However, of the 213 patients who received the booster vaccine, 22 patients (10.3%) were infected with COVID-19, and 18 patients (81.8%) had mild disease; these cases included the patients who remained seronegative. Thus, we believe that booster vaccinations may help in reducing the severity of Omicron variant COVID-19 infection in patients with B-NHL.

Helicobacter pylori eradication treatment for primary gastric diffuse large B-cell lymphoma: A single-center analysis.

BACKGROUND: Unlike the already established effect of Helicobacter pylori (H. pylori) eradication on gastric mucosa-associated lymphoid tissue (MALT) lymphoma, its therapeutic effect on primary gastric diffuse large B-cell lymphoma (DLBCL) is still unclear. AIM: To clarify the efficacy of H. pylori eradication treatment for primary gastric DLBCL. METHODS: We reported on 3 new cases, and added them to 3 previously reported cases. We analyzed the usefulness of H. pylori eradication treatment for gastric DLBCL for a total of 6 cases at our center. RESULTS: Of the 6 patients (27-90 years old, 3 males and 3 females), all 3 patients with single lesions (one transformed from MALT lymphoma) achieved complete remission (CR) after H. pylori eradication. Regarding the 2 newly reported cases, CR was maintained for more than 6 years with eradication treatment alone. In contrast, none of the 3 patients with 2 lesions achieved CR. In 1 newly reported case, endoscopic CR was achieved in one lesion, while stable disease was obtained in the other lesion. Two patients with progressive disease responded to standard chemotherapy ± radiation and remained in CR for more than 6 years. CONCLUSION: We believe it is worthwhile to attempt H. pylori eradication for elderly patients with primary gastric DLBCL in a single lesion with a small tumor burden.

[Brentuximab Vedotin, Doxorubicin, Vinblastine, Dacarbazine(A+AVD)Therapy for Classical Hodgkin Lymphoma- A Single-Institution Experience].

The JSH Practical Guidelines for Hematological Malignancies, 2018 expanded edition, newly adopted brentuximab vedotin, doxorubicin, vinblastine, dacarbazine(A+AVD)protocol as a standard treatment for advanced-stage classical Hodgkin lymphoma(CHL). Therefore, this retrospective analysis compared 15 patients who received A+AVD therapy with 21 patients who received doxorubicin, bleomycin, vinblastine, dacarbazine(ABVD)therapy. All patients were newly diagnosed with CHL and received induction therapy between April 2015 and June 2022 in our hospital. All except 1 patient of the A+AVD group had advanced-stage CHL. The median age was 63(23-85)years. The estimated 2-year overall survival of the A+AVD group was better than that of the ABVD group which included 6 patients with clinical stage Ⅲ or higher CHL (100% vs 66.7%, p=0.047). In contrast, there was no significant difference in the complete response rate(53.8% vs 100%, p=0.109)between the 2 groups. The overall response rate after first-line treatment(69.2% vs 100%, p=0.255), and the estimated 2-year progression-free survival(70.1% vs 66.7%, p=0.321)between the A+AVD and the ABVD groups were similar.

Dominant-negative type of IKZF1 deletion showed a favorable prognosis in adult B-cell acute lymphoblastic leukemia.

IKZF1 deletion is a recurrent genomic alteration in B-cell acute lymphoblastic leukemia (B-ALL) and is divided into dominant-negative (DN) and loss of function (LOF) deletions. The prognostic impact of each deletion has not been fully elucidated. We retrospectively analyzed 117 patients with adult B-ALL including 60 patients with BCR::ABL1-positive B-ALL and 57 patients with BCR::ABL1-negative B-ALL by the fluorescence in situ hybridization (FISH) method for IKZF1 deletion and multiplex PCR for the 4 most common IKZF1 deletions (∆4-7, ∆2-7, ∆2-8, and ∆4-8). Samples, in which IKZF1 deletion was detected by FISH but a specific type of deletion was not identified by the PCR, were categorized as "other." Patients were classified into a DN group that had at least 1 allele of ∆4-7 (n = 23), LOF and other group (n = 40), and wildtype group (n = 54). DN type IKZF1 deletions were found in 33.3% of BCR::ABL1-positive cases and 5.2% of BCR::ABL1-negative cases. LOF and other type IKZF1 deletions were found in 43.4% of BCR::ABL1-positive cases and 24.6% of BCR::ABL1-negative cases. Patients with the DN group showed significantly higher overall survival (OS) than that of the LOF and other and WT groups (P = 0.011). Multivariate analysis including age, WBC counts, complex karyotype, and DN type IKZF1 deletion showed that the DN type of IKZF1 deletion (HR = 0.22, P = 0.013) had a positive impact and age ≥ 65 (HR = 1.92, P = 0.029) had a negative impact on OS. The prognostic impact of IKZF1 deletion depends on the type of deletion and DN type of IKZF1 deletion showed better prognosis in adult B-ALL patients.Clinical trial registration This study was part of a prospective observational study (Hokkaido Leukemia Net, UMIN000048611). It was conducted in compliance with ethical principles based on the Helsinki Declaration and was approved by the institutional review board of Hokkaido University Hospital (#015-0344).

Booster effect of a third mRNA-based COVID-19 vaccine dose in patients with myeloid malignancies.

BACKGROUND: We have reported that seroconversion rates after the second dose of mRNA-based COVID-19 vaccines for myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) were 100% and 95% respectively, with no significant difference from healthy controls (HCs).However, there are very limited data for the response to a third vaccine dose in those patients. AIMS: In this complementary study, we investigated the booster effect of a third mRNA-based COVID-19 vaccine dose in patients with myeloid malignancies. MATERIALS & METHODS: A total 58 patients including 20 patients with MDS and 38 patients with AML were enrolled. Anti-SARS-CoV-2S immunoassays were performed at 3, 6, and 9 months after the second vaccine dose. RESULTS: Seventy-five percent of the MDS patients and 37% of the AML patients were receiving active treatment at the time of the third vaccination. Both the initial and third vaccine response in AML patients were comparable to those in HCs. In MDS patients, although the initial vaccine immunogenicity was inferior to that in HCs and AML patients, the third vaccine improved the response to a level not inferior to those in HCs and AML patients. Of note, the third vaccine resulted in a significant increase of antibodies in actively treated MDS patients who had shown a response inferior to that in untreated patients after two doses of vaccination. DISCUSSION: In patients with myeloid malignancies, the third vaccine dose showed a booster effect, and disease- and therapy-related factors associated with the booster response have been identified. CONCLUSION: The third dose of an mRNA-based COVID-19 vaccine showed a booster effect in patients with myeloid malignancies. Such a good booster response has not been reported in other haematological malignancies.

Clinical implications of NUP98::NSD1 fusion at diagnosis in adult FLT3-ITD positive AML.

OBJECTIVES: The cryptic fusion oncogene NUP98::NSD1 is known to be associated with FLT3-ITD mutation in acute myeloid leukemia (AML), and an independent poor prognostic factor in pediatric AML. However, there are little data regarding the clinical significance of NUP98::NSD1 in adult cohort. METHODS: We conducted a multicenter retrospective study to investigate the prevalence, clinical characteristics, and prognostic impact of NUP98::NSD1 in adult FLT3-ITD-positive AML patients. RESULTS: In a total of 97 FLT3-ITD-positive AML patients, six cases (6.2%) were found to harbor the NUP98::NSD1 fusion transcript. NUP98::NSD1 positive cases had significantly higher platelet counts and a higher frequency of FAB-M4 morphology than NUP98::NSD1 negative cases. NUP98::NSD1 was found to be mutually exclusive with NPM1 mutation, and was accompanied by the WT1 mutation in three of the six cases. The presence of NUP98::NSD1 fusion at the time of diagnosis predicted poor response to cytarabine-anthracycline-based intensive induction chemotherapy (induction failure rate: 83% vs. 36%, p = .038). Five of the six cases with NUP98::NSD1 underwent allogeneic hematopoietic stem cell transplantation (HSCT). Two of the five cases have successfully maintained remission, with one of them being rescued through a second HSCT. CONCLUSIONS: Detecting NUP98::NSD1 in adult FLT3-ITD-positive AML is crucial to recognizing chemotherapy-resistant group.

New onset of hypomegakaryocytic thrombocytopenia with the potential for progression to aplastic anemia after BNT162b2 mRNA COVID-19 vaccination.

Vaccination with a coronavirus disease-2019 (COVID-19) vaccine is an effective public health measure for reducing the risk of infection and severe complications from COVID-19. However, serious hematological complications after COVID-19 vaccination have been reported. Here, we report a case of new-onset hypomegakaryocytic thrombocytopenia (HMT) with the potential for progression to aplastic anemia (AA) that developed in a 46-year-old man 4 days after the fourth mRNA COVID-19 vaccination. Platelet count rapidly decreased after vaccination and white blood cell count declined subsequently. Bone marrow examination immediately after disease onset showed severely hypocellular marrow (cellularity of almost 0%) in the absence of fibrosis, findings that were consistent with AA. Since the severity of pancytopenia did not meet the diagnostic criteria for AA, the patient was diagnosed with HMT that could progress to AA. Treatment with eltrombopag and cyclosporine was started immediately after diagnosis and cytopenia improved. Although it is difficult to determine whether the post-vaccination cytopenia was vaccine induced or accidental because the association was chronological, vaccination with an mRNA-based COVID-19 vaccine may be associated with development of HMT/AA. Therefore, physicians should be aware of this rare, but serious adverse event and promptly provide appropriate treatment.

Development of a new HISCL automated CXCL9 immunoassay.

C-X-C motif chemokine ligand 9 (CXCL9), a candidate biomarker, reflects type 1 (T1) inflammation pathology. Here, we report the analytical performance and clinical characteristics of a new CXCL9 reagent for a fully automated immunoassay device. We evaluated the limits of blank, detection, and quantitation (LoQ) along with other efficacy parameters, and the ability of the assay to report patient health, COVID-19 status, and the presence of asthma and/or interstitial lung diseases (ILDs). The coefficient of variation for 5-day total precision using two instruments was 7% across two controls, serum, and plasma panels. LoQ of 2.2 pg/mL suggested the efficacy of the assay in detecting T1 inflammation in plasma or serum; no cross-reactivity or interference was observed. We identified high serum CXCL9 levels in samples from patients with acute COVID-19 infections (n = 57), chronic bird-related hypersensitivity pneumonitis (n = 61), asthma (n = 194), and ILDs (n = 84) compared to healthy individuals (< 39.0 pg/mL). Furthermore, CXCL9 levels increased with age in asthma patients, and an opposite trend was observed for T2 inflammatory factors. These results suggest the utility of the automated CXCL9 immunoassay for measuring CXCL9 in clinical samples and reflect its role in T1 inflammation.

Subclinical minute FLT3-ITD clone can be detected in clinically FLT3-ITD-negative acute myeloid leukaemia at diagnosis.

Recent advances in next-generation sequencing (NGS) have enabled the detection of subclinical minute FLT3-ITD. We selected 74 newly diagnosed, cytogenetically normal acute myeloid leukaemia (AML) samples in which FLT3-ITD was not detected by gel electrophoresis. We sequenced them using NGS and found minute FLT3-ITDs in 19 cases. We compared cases with clinically relevant FLT3-ITD (n = 37), cases with minute FLT3-ITD (n = 19) and cases without detectable FLT3-ITD (n = 55). Molecular characteristics (location and length) of minute FLT3-ITD were similar to those of clinically relevant FLT3-ITD. Survival of cases with minute FLT3-ITD was similar to that of cases without detectable FLT3-ITD, whereas the relapse rate within 1 year after onset was significantly higher in cases with minute FLT3-ITD. We followed 18 relapsed samples of cases with clinically FLT3-ITD-negative at diagnosis. Two of 3 cases with minute FLT3-ITD relapsed with progression to clinically relevant FLT3-ITD. Two of 15 cases in which FLT3-ITD was not detected by NGS relapsed with the emergence of minute FLT3-ITD, and one of them showed progression to clinically relevant FLT3-ITD at the second relapse. We revealed the clonal dynamics of subclinical minute FLT3-ITD in clinically FLT3-ITD-negative AML. Minute FLT3-ITD at the initial AML can expand to become a dominant clone at relapse.

Anti-CD20 antibodies and bendamustine attenuate humoral immunity to COVID-19 vaccination in patients with B-cell non-Hodgkin lymphoma.

Serologic responses of COVID-19 vaccine are impaired in patients with B-cell lymphoma, especially those who had recently been treated with anti-CD20 monoclonal antibodies. However, it is still unclear whether those patients develop an immune response following vaccination. We investigated the efficacy of vaccination against SARS-CoV-2 in 171 patients with B-cell non-Hodgkin lymphoma (B-NHL) who received two doses of an mRNA-based COVID-19 vaccine and we compared the efficacy of vaccination to that in 166 healthy controls. Antibody titers were measured 3 months after administration of the second vaccine dose. Patients with B-NHL showed a significantly lower seroconversion rate and a lower median antibody titer than those in healthy controls. The antibody titers showed correlations with the period from the last anti-CD20 antibody treatment to vaccination, the period from the last bendamustine treatment to vaccination and serum IgM level. The serologic response rates and median antibody titers were significantly different between diffuse large B-cell lymphoma (DLBCL) patients in whom anti-CD20 antibody treatment was completed within 9 months before vaccination and follicular lymphoma (FL) patients in whom anti-CD20 antibody treatment was completed within 15 months before vaccination. Moreover, the serologic response rates and median antibody titers were significantly different among FL patients in whom bendamustine treatment was completed within 33 months before vaccination. We demonstrated that B-NHL patients who were recently treated with anti-CD20 antibodies and bendamustine had a diminished humoral response to COVID-19 vaccination. UMIN 000,045,267.

Humoral response to mRNA-based COVID-19 vaccine and booster effect of a third dose in patients with mature T cell and NK-cell neoplasms.

Patients with lymphoid malignancies have impaired humoral immunity caused by the disease itself and its treatment, placing them at risk for severe coronavirus disease-19 (COVID-19) and reduced response to vaccination. However, data for COVID-19 vaccine responses in patients with mature T cell and NK-cell neoplasms are very limited. In this study of 19 patients with mature T/NK-cell neoplasms, anti-severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike antibodies were measured at 3 months, 6 months, and 9 months after the second mRNA-based vaccination. At the time of the second and third vaccinations, 31.6% and 15.4% of the patients were receiving active treatment. All patients received the primary vaccine dose and the third vaccination rate was 68.4%. In patients with mature T/NK-cell neoplasms, both seroconversion rate (p < 0.01) and antibody titers (p < 0.01) after the second vaccination were significantly lower than those in healthy controls (HC). In individuals who received the booster dose, patients had significantly lower antibody titers than those in HC (p < 0.01); however, the seroconversion rate in patients was 100%, which was the same as that in HC. The booster vaccine resulted in a significant increase of antibodies in elderly patients who had shown a response that was inferior to that in younger patients after two doses of vaccination. Since higher antibody titers and higher seroconversion rate reduced the incidence of infection and mortality, vaccination more than three times may have the advantage for patients with mature T/NK-cell neoplasms, especially in elderly patients. Clinical trial registration number: UMIN 000,045,267 (August 26th, 2021), 000,048,764 (August 26th, 2022).

Prognostic impact of FLT3-ITD, NPM1 mutation and CEBPA bZIP domain mutation in cytogenetically normal acute myeloid leukemia: a Hokkaido Leukemia Net study.

Mutation status of FLT3, NPM1, and CEBPA is used to classify the prognosis of acute myeloid leukemia, but its significance in patients with cytogenetically normal (CN) AML is unclear. We prospectively analyzed these genes in 295 patients with CN-AML and identified 76 (25.8%) FLT3-ITD, 113 (38.3%) NPM1 mutations, and 30 (10.2%) CEBPA biallelic mutations. We found that patients with FLT3-ITD had a poor prognosis at any age, while patients with CEBPA biallelic mutation were younger and had a better prognosis. FLT3-ITD and NPM1 mutations were correlated, and the favorable prognostic impact of being FLT3-ITD negative and NPM1 mutation positive was evident only in patients aged 65 years or more. For CEBPA, 86.7% of the patients with biallelic mutation and 9.1% of patients with the single allele mutation had in-frame mutations in the bZIP domain, which were strongly associated with a favorable prognosis. Multivariate analysis showed that age < 65 years, FLT3-ITD and CEBPA bZIP in-frame mutation were independent prognostic factors. The results suggest that analyzing these gene mutations at diagnosis can inform selection of the optimal intensity of therapy for patients with CN-AML.

Thiotepa-based high-dose chemotherapy with autologous stem cell transplantation for neurolymphomatosis.

Neurolymphomatosis (NL) is a rare clinical entity characterized by lymphomatous infiltration of the peripheral nervous system. According to recent retrospective data, consolidative high-dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) may be beneficial for NL. However, few reports to date have discussed optimal conditioning regimens. Herein, we report two cases of NL in patients with relapsed intravascular large B-cell lymphoma who received consolidative thiotepa-containing HDC-ASCT. Case 1: A 56-year-old woman who relapsed 2 months after the first complete remission (CR) and underwent ASCT. Case 2: A 65-year-old woman who relapsed 8 months after the first CR and underwent ASCT. Both patients engrafted. Time to neutrophil engraftment was 10 and 12 days after HDC-ASCT, and CR was sustained for 26 and 18 months, respectively, as of the last follow-up. Although there is little evidence supporting the utility of thiotepa-based HDC-ASCT in patients with NL, the results of this case report suggest that further studies are warranted to determine its efficacy in this setting.

Humoral response to mRNA-based COVID-19 vaccine in patients with immune thrombocytopenia.

Data for COVID-19 vaccine response in patients with immune thrombocytopenia (ITP) are very limited. In a study of 28 patients with ITP, anti-severe acute respiratory syndrome coronavirus 2 spike antibody titres were measured after vaccination. The seroconversion rate for ITP patients was 91.3%, comparable to that in healthy controls (HCs). However, the antibody titre in ITP patients was significantly lower than that in HCs and declined with ageing. Furthermore, the antibody titre in ITP patients who received a minimum prednisolone dose of at least 5 mg/day at any time-point at or after initial vaccination was lower than that in other patients.

Clinical features of complex karyotype in newly diagnosed acute myeloid leukemia.

Complex karyotype acute myeloid leukemia (CK-AML) has been classified as an adverse-risk subtype. Although a few reports have further classified CK-AML as typical (including monosomy of chromosomes 5, 7 and 17 or deletion of 5q, 7q and/or 17p) or atypical, the clinical features of these subtypes in Japanese patients remain unclear. We retrospectively analyzed a total of 115 patients with CK-AML, including 77 with typical CK-AML and 38 with atypical CK-AML. Median overall survival (OS) was significantly shorter in patients with typical CK-AML than atypical CK-AML (143 days vs. 369 days, P = 0.009). Among patients with typical CK-AML, those with monosomy 17 or deletion of 17p had significantly shorter OS than patients without such abnormalities (105 days vs. 165 days, P = 0.033). TP53 mutations were more predominant in patients with typical CK-AML than in patients with atypical CK-AML (69.7% vs. 32.4%, P < 0.001). Patients with typical CK-AML had a poor prognosis regardless of TP53 mutation status. Among patients with atypical CK-AML, however, prognosis was worse for those with the TP53 mutation than those without the mutation. In conclusion, prognosis is extremely poor for both typical CK-AML and atypical CK-AML with TP53 mutation.

Re-evaluation of over-the-counter histamine H1-receptor antagonists based on their effects on murine models of allergen-induced nasal hyperresponsiveness.

T cells play an essential role in the development of allergen-induced nasal hyperresponsiveness (NHR), a pathophysiological response in allergic rhinitis. The effects of histamine H1-receptor antagonists (antihistamines) on murine NHR models were investigated. Intragastric epinastine, fexofenadine, and loratadine administration suppressed allergen-induced immediate nasal response but not NHR in immunized mice. Regardless of the alleviation of stimulation-induced Th2 cytokine expression by loratadine and desloratadine in vitro, allergen-induced NHR and nasal eosinophil infiltration in Th2 cell-transferred mice were unaffected by loratadine in vivo. This influence on T cell-mediated NHR was excluded from the pharmacological effects of antihistamines.

[Steroid resistance of severe asthma - mechanisms and therapeutic targets].

Asthma therapy in general has improved a lot in recent years, but it is still a major problem that severe asthma, which accounts for 10 to 20%, still suffers from strong symptoms on a daily basis despite all therapeutic agents used in combination. American SARP and European ENFUMOSA started in 2000 to advance pathophysiological insights of severe asthma. Clinical usage of antibodies and inhibitors against IgE, TNF, IL-5, IL-4, IL-13, and TSLP are also accumulating. Some of these molecular-targeted drugs improve respiratory function and reduce acute exacerbations in patients with severe asthma. Until now, cytokines have been assumed to be involved in chronic inflammation, but it is also interesting to elucidate the pathways of how cytokines are involved in respiratory function and acute exacerbations. We registered approximately 100 steroid-dependent asthma patients in Japan. Although long-lasting poor control of the disease was considered the cause of severe asthma in the past, steroid dependence in one third of the cases occurred within 2-3 years after the onset. Steroid resistance seems a key process from the early stage of the disease. Steroid resistance of T cell level was induced by extracellular co-stimulation and cytokine signals. The inhibition may improve steroid sensitivity and treat steroid-resistant asthma. Therefore, we established a steroid-resistant asthma model for the first time by transferring steroid resistant T cell clones, and analyzed the steroid sensitivity recovery effect of CTLA4-Ig. In addition, a multicenter, double-blind, placebo-controlled exploratory trial was performed as a POC study investigating the efficacy of abatacept in treatment-resistant severe asthma. Elucidation of the pathophysiology and mechanism by which steroids do not work is expected to be a breakthrough for the prevention and treatment of severe asthma.