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.

Prolonged shedding of viable SARS-CoV-2 in immunocompromised patients with haematological malignancies: A prospective study.

Prolonged SARS-CoV-2 infection in immunocompromised individuals has been scattered, but the details remain unclear. We conducted a prospective study with 26 COVID-19 patients with haematological malignancies to determine viral shedding kinetics and characteristics. We obtained nasopharyngeal swabs from the patients 21-28 days post-onset for a PCR test and performed virus isolation from the PCR-positive samples. A viable virus was detected in five patients (19.2%), all of whom had malignant lymphoma. Those patients had significantly lower CD4+ T-cell counts than the PCR-negative patients. A comparison of previous chemotherapy showed that anti-CD20 antibodies and bendamustine may be risk factors for prolonged viral shedding.

Whole-genome CRISPR screening identifies molecular mechanisms of PD-L1 expression in adult T-cell leukemia/lymphoma.

ABSTRACT: Adult T-cell leukemia/lymphoma (ATLL) is an aggressive T-cell malignancy with a poor prognosis and limited treatment options. Programmed cell death ligand 1(PD-L1) is recognized to be involved in the pathobiology of ATLL. However, what molecules control PD-L1 expression and whether genetic or pharmacological intervention might modify PD-L1 expression in ATLL cells are still unknown. To comprehend the regulatory mechanisms of PD-L1 expression in ATLL cells, we performed unbiased genome-wide clustered regularly interspaced short palindromic repeat (CRISPR) screening in this work. In ATLL cells, we discovered that the neddylation-associated genes NEDD8, NAE1, UBA3, and CUL3 negatively regulated PD-L1 expression, whereas STAT3 positively did so. We verified, in line with the genetic results, that treatment with the JAK1/2 inhibitor ruxolitinib or the neddylation pathway inhibitor pevonedistat resulted in a decrease in PD-L1 expression in ATLL cells or an increase in it, respectively. It is significant that these results held true regardless of whether ATLL cells had the PD-L1 3' structural variant, a known genetic anomaly that promotes PD-L1 overexpression in certain patients with primary ATLL. Pevonedistat alone showed cytotoxicity for ATLL cells, but compared with each single modality, pevonedistat improved the cytotoxic effects of the anti-PD-L1 monoclonal antibody avelumab and chimeric antigen receptor (CAR) T cells targeting PD-L1 in vitro. As a result, our work provided insight into a portion of the complex regulatory mechanisms governing PD-L1 expression in ATLL cells and demonstrated the in vitro preliminary preclinical efficacy of PD-L1-directed immunotherapies by using pevonedistat to upregulate PD-L1 in ATLL cells.

Prognostic Value of Hematogones in Patients With Hematopoietic Disorders After Allogeneic Hematopoietic Stem Cell Transplantation: A Systematic Review and Meta-Analysis.

This systematic review and meta-analysis aimed to determine whether hematogones in patients with hematopoietic disorders after allogeneic hematopoietic stem cell transplantation (allo-HSCT) are associated with clinical outcomes. We searched the MEDLINE, Embase, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and World Health Organization International Clinical Trials Registry Platform databases from their inception to March 2023. The primary outcome in the summary of findings was three-year relapse-free survival (RFS), and secondary outcomes in the summary of findings included three-year relapse, non-relapse mortality (NRM), overall survival (OS), acute and chronic graft-versus-host disease (GVHD), and infection. The certainty of evidence was determined using the grading of recommendation assessment, development, and evaluation approaches. A systematic review and meta-analysis of outcome measures were conducted using a random-effects model. This study protocol was registered in the Open Science Framework. A total of six studies (including 888 patients) were included in the meta-analysis. Hematogones were related to favorable three-year RFS (risk ratio (RR) = 1.84; 95% confidence interval (CI) = 1.01 to 3.34) and favorable NRM (RR = 0.14; 95% CI = 0.04 to 0.51), OS (RR = 1.51; 95% CI = 1.13 to 2.02), and acute GVHD (RR = 0.44; 95% CI = 0.33 to 0.59). The certainty of the evidence was low for RFS, NRM, OS, and acute GVHD. Evidence regarding the association between hematogones, relapse, and infections is uncertain. Hematogones may be a prognostic factor for long-term prognosis and acute adverse events in patients with hematopoietic disorders after allo-HSCT. Further studies are required to address the long-term life-threatening events.

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.

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).

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.

Duodenal-type follicular lymphoma more than 10 years after treatment intervention: A retrospective single-center analysis.

BACKGROUND: Duodenal-type follicular lymphoma (D-FL) has been recognized as a rare entity that accounts for approximately 4% of primary gastrointestinal lymphomas. D-FL follows an indolent clinical course compared with common nodal FL and is generally considered to have a better prognosis. Therefore, the "watch and wait" approach is frequently adopted as the treatment method. Alternatively, there is an option to actively intervene in D-FL. However, the long-term outcomes of such cases are poorly understood. AIM: To clarify the clinical outcomes after long-term follow-up in cases of D-FL with treatment intervention. METHODS: We retrospectively analyzed patients who met the following criteria: the lesion was confirmed by endoscopy, the diagnosis of D-FL was confirmed histopathologically, and the patient was followed-up for more than 10 years after the intervention at our center. RESULTS: We identified 5 cases of D-FL. Two patients showed a small amount of bone marrow involvement (Stage IV). Rituximab was used as a treatment for remission in all 5 patients. It was also used in combination with chemotherapy in 2 Stage IV patients as well as for maintenance treatment. Radiation therapy was performed in 2 cases, which was followed by complete remission (CR). Eventually, all 5 patients achieved CR and survived for more than 10 years. However, 3 patients experienced recurrence. One patient achieved a second CR by retreatment, and in another case, the lesion showed spontaneous disappearance. The remaining patient had systemic widespread recurrence 13 years after the first CR. Biopsy results suggested that the FL lesions were transformed into diffuse large B-cell lymphoma. The patient died 4 years later despite receiving various chemotherapies. CONCLUSION: In this study, the treatment for patients of D-FL in Stage IV was successful. In the future, criteria for how to treat "advanced" D-FL should be established based on additional cases. This study of patients with D-FL indicates that whole-body follow-up examinations should continue for a long time due to a fatal recurrence 13 years after reaching CR.

Genome-wide CRISPR screens identify CD48 defining susceptibility to NK cytotoxicity in peripheral T-cell lymphomas.

Adult T-cell leukemia/lymphoma (ATLL) is one of the aggressive peripheral T-cell neoplasms with a poor prognosis. Accumulating evidence demonstrates that escape from adaptive immunity is a hallmark of ATLL pathogenesis. However, the mechanisms by which ATLL cells evade natural killer (NK)-cell-mediated immunity have been poorly understood. Here we show that CD48 expression in ATLL cells determines the sensitivity for NK-cell-mediated cytotoxicity against ATLL cells. We performed unbiased genome-wide clustered regularly interspaced short palindromic repeat (CRISPR) screening using 2 ATLL-derived cell lines and discovered CD48 as one of the best-enriched genes whose knockout conferred resistance to YT1-NK cell line-mediated cytotoxicity. The ability of CD48-knockout ATLL cells to evade NK-cell effector function was confirmed using human primary NK cells with reduced interferon-γ (IFNγ) induction and degranulation. We found that primary ATLL cells had reduced CD48 expression along with disease progression. Furthermore, other subgroups among aggressive peripheral T-cell lymphomas (PTCLs) also expressed lower concentrations of CD48 than normal T cells, suggesting that CD48 is a key molecule in malignant T-cell evasion of NK-cell surveillance. Thus, this study demonstrates that CD48 expression is likely critical for malignant T-cell lymphoma cell regulation of NK-cell-mediated immunity and provides a rationale for future evaluation of CD48 as a molecular biomarker in NK-cell-associated immunotherapies.

Gilteritinib enhances graft-versus-leukemia effects against FLT3-ITD mutant leukemia after allogeneic hematopoietic stem cell transplantation.

Allogeneic hematopoietic stem cell transplantation (allo-SCT) is a potentially curative therapy for FLT3 internal tandem duplication mutant (FLT3-ITD+) acute myeloid leukemia, but relapse rate is high. A recent study showed that sorafenib, a first generation FLT3 and multikinase inhibitor, enhanced graft-versus-leukemia (GVL) effects against FLT3-ITD+ leukemia via interleukin-15 (IL-15) production. However, it remains to be clarified whether this effect could be mediated by selective FLT3 inhibition. We investigated whether gilteritinib, a selective FLT3 inhibitor, could enhance GVL effects against FLT3-ITD transfected Ba/F3 leukemia (Ba/F3-FLT3-ITD) in mice. Oral administration of gilteritinib from day +5 to +14 after allo-SCT reduced expression of the co-inhibitory receptors PD-1 and TIGIT on donor CD8+ T cells and enhanced IL-15 expression in Ba/F3-FLT3-ITD. Bioluminescent imaging using luciferase-transfected Ba/F3-FLT3-ITD demonstrated that gilteritinib significantly suppressed leukemia expansion after allo-SCT, whereas it did not impact the morbidity or mortality of graft-versus-host disease (GVHD), resulting in significant improvement of overall survival. In conclusion, short-term administration of gilteritinib after allo-SCT enhanced GVL effects against FLT3-ITD+ leukemia without exacerbating GVHD.

Humoral response to mRNA-based COVID-19 vaccine in patients with myeloid malignancies.

Data on the response to the COVID-19 vaccine in patients with myeloid malignancy, who are at severe risk in case of infection, have not emerged. In a study of 69 patients with myeloid malignancies, including 46 patients with acute myeloid leukaemia (AML) and 23 patients with myelodysplastic syndrome (MDS), anti-spike SARS-CoV-2 antibody titres were measured 3 months after the second mRNA-based vaccination. Seroconversion rates for AML and MDS were 94.7% and 100% respectively, with no significant difference from healthy controls (HCs). Patients with MDS showed a significantly lower antibody titre than that in HCs or AML patients. In AML patients, the antibody titres were comparable to those in HCs when treatment was completed, but lower in patients under maintenance therapy. The response to COVID-19 vaccine appears to be related to disease and treatment status. Patients with myeloid malignancies may be more responsive to vaccines than patients with lymphoid malignancies.

Genome-wide CRISPR screen identifies CDK6 as a therapeutic target in adult T-cell leukemia/lymphoma.

Adult T-cell leukemia/lymphoma (ATLL) is an aggressive T-cell malignancy with a poor prognosis with current therapy. Here we report genome-wide CRISPR-Cas9 screening of ATLL models, which identified CDK6, CCND2, BATF3, JUNB, STAT3, and IL10RB as genes that are essential for the proliferation and/or survival of ATLL cells. As a single agent, the CDK6 inhibitor palbociclib induced cell cycle arrest and apoptosis in ATLL models with wild-type TP53. ATLL models that had inactivated TP53 genetically were relatively resistant to palbociclib owing to compensatory CDK2 activity, and this resistance could be reversed by APR-246, a small molecule activator of mutant TP53. The CRISPR-Cas9 screen further highlighted the dependence of ATLL cells on mTORC1 signaling. Treatment of ATLL cells with palbociclib in combination with mTORC1 inhibitors was synergistically toxic irrespective of the TP53 status. This work defines CDK6 as a novel therapeutic target for ATLL and supports the clinical evaluation of palbociclib in combination with mTORC1 inhibitors in this recalcitrant malignancy.

Multiple Colorectal Mucosa-Associated Lymphoid Tissue Lymphoma Successfully Treated with Chemotherapy.

The standard treatment for colorectal mucosa-associated lymphoid tissue (MALT) lymphoma has not yet been established due to the rarity of the disease. Here, we report a case of long-term response to chemotherapy for colorectal MALT lymphoma (stage I). A 77-year-old frail female patient with diabetes mellitus and dementia developed melena of unknown etiology, and a colonoscopy was performed at a nearby hospital. A biopsy suggested malignant lymphoma, and she was referred to our department. As a result of re-examination of colonoscopy, a total of 3 submucosal tumor-like lesions were confirmed. Of these, a biopsy of the lesions in the ascending colon and rectum was performed, and MALT lymphoma was diagnosed on the basis of the histopathological findings. Following close examination, no other lymphoma lesions were found, and the patient was diagnosed with primary colorectal MALT lymphoma, stage I. After 1 course of R-THP-COP chemotherapy (rituximab + cyclophosphamide, pirarubicin, vincristine, and prednisone), the rectal lesion was confirmed to have almost disappeared endoscopically, and lymphoma cells were not found histopathologically. The patient was determined to be in complete remission (CR). However, due to hematological toxicity and a slight worsening of glucose control, the second chemotherapy course was changed to the BR regimen (rituximab + bendamustine), and 4 courses were performed (5 total courses of chemotherapy). Currently, >3 years have passed since reaching CR, and the patient is alive without recurrence.

Targeting the HTLV-I-Regulated BATF3/IRF4 Transcriptional Network in Adult T Cell Leukemia/Lymphoma.

Adult T cell leukemia/lymphoma (ATLL) is a frequently incurable disease associated with the human lymphotropic virus type I (HTLV-I). RNAi screening of ATLL lines revealed that their proliferation depends on BATF3 and IRF4, which cooperatively drive ATLL-specific gene expression. HBZ, the only HTLV-I encoded transcription factor that is expressed in all ATLL cases, binds to an ATLL-specific BATF3 super-enhancer and thereby regulates the expression of BATF3 and its downstream targets, including MYC. Inhibitors of bromodomain-and-extra-terminal-domain (BET) chromatin proteins collapsed the transcriptional network directed by HBZ and BATF3, and were consequently toxic for ATLL cell lines, patient samples, and xenografts. Our study demonstrates that the HTLV-I oncogenic retrovirus exploits a regulatory module that can be attacked therapeutically with BET inhibitors.

The association between the incidence of intestinal graft-vs-host disease and antibiotic use after allogeneic hematopoietic stem cell transplantation.

Intestinal microbiota plays an important role in the regulation of allogeneic immune reaction after allogeneic hematopoietic stem cell transplantation (allo-SCT). Intestinal graft-vs-host disease (GVHD) is one of the major causes of mortality after allo-SCT and often complicated with intestinal dysbiosis. Recent studies suggest that antibiotic-induced dysbiosis is a risk factor for intestinal GVHD. We retrospectively evaluated the impacts of antibiotic use on the incidence of intestinal GVHD occurring before day 100 after allo-SCT. Among 213 patients who underwent allo-SCT, 200 patients achieving engraftment were analyzed. Antibiotics were classified into carbapenem, quinolone, penicillin, cephem, and glycopeptide. Among 128 patients who developed acute GVHD, intestinal GVHD developed in 36 patients. Patients with intestinal GVHD received significantly longer administration of carbapenem and glycopeptide compared to those without it in periengraftment period. In multivariate analysis, use of carbapenem for greater than 7 days was associated with an increased risk of intestinal GVHD. However, use of antibiotics for greater than 7 days was not associated with poor overall survival and high nonrelapse mortality. Long use of carbapenem in periengraftment period may be a risk for intestinal GVHD. Prospective studies are required to validate our findings.

Hematogones Predict Better Outcome in Allogeneic Hematopoietic Stem Cell Transplantation Irrespective of Graft Sources.

Benign precursors of B lymphocytes, termed hematogones, are observed in the regenerative state of hematopoiesis following chemotherapy or allogeneic hematopoietic stem cell transplantation (allo-HSCT). Previous studies have demonstrated that expansion of hematogones correlates with better clinical outcomes after allo-HSCT. We retrospectively analyzed the association between hematogones and clinical outcomes in 309 consecutive patients who underwent allo-HSCT, which is the largest population-based cohort reported so far. The incidence of hematogones was significantly higher in complete remission (CR) patients at the time of transplantation than in non-CR patients, after myeloablative conditioning than after reduced-intensity conditioning, with tacrolimus-based graft-versus-host disease (GVHD) prophylaxis than with cyclosporine-based prophylaxis, and with disease other than malignant lymphoma (all P < .05). Patients with hematogones developed less acute GVHD and infections than did those without them (P < .05). Emergence of hematogones was associated with superior GVHD-free relapse-free survival and lower nonrelapse mortality, and was an independent prognostic factor for overall survival, irrespective of donor sources.