Clinical characteristics and outcomes of Epstein-Barr virus viral load after allogeneic hematopoietic stem cell transplantation.

Epstein-Barr virus (EBV) reactivation can occur following allogenic hematopoietic stem cell transplantation (allo-HSCT). However, the clinical characteristics and outcomes of EBV-viral load are not well known. Thus, we retrospectively analyzed the clinical features and prognostic impact of the EBV viral load in 121 allo-HSCT recipients from our hospital. EBV DNA quantification was performed in whole blood after transplantation. Patients were grouped based on whether EBV DNA quantification reached > 1000 copies/mL during follow-up (N = 50) or not (N = 71). Patients with EBV > 1000 EBV copies/mL were relatively more common in the groups with graft versus host disease (GVHD) prophylaxis including ATG, haploidentical donor type, peripheral blood as a donor source, and acute GVHD II-IV. The 20-month OS and DFS were not significantly different between patients with < 1000 EBV copies/mL and patients with > 1000 EBV copies/mL (20-month OS, 56.0% vs. 60.6%; p = 0.503, 20-month DFS, 50.0% vs. 57.7%; p = 0.179). Immunosuppressant (ISS) dose reduction was achieved after the maximum increase in EBV in 41/50 (82%) patients. Additionally, 30/50 (60%) patients achieved a 50% dose reduction or no restarting of ISS within 3 months of the maximum EBV increase. Among cases wherein EBV DNA quantification reached > 1000 copies/mL, those that achieved rapid dose reduction of ISS tended to have longer overall survival ("not reached" vs 5.4 months, p < 0.001) and disease-free survival (88.4 months vs 5.3 months, p < 0.001) than those in patients who did not. Our data highlight the importance of rapid ISS reduction in post-transplant EBV reactivation.

Clinical Characteristics and Outcomes of Cyclin D1-Positive AL Amyloidosis.

OBJECTIVES: To demonstrate the clinical features and prognostic impact of cyclin D1 positivity in patients with amyloid light chain amyloidosis (AL). METHODS: We consecutively included 71 patients diagnosed with AL with cyclin D1 positivity between February 2008 and January 2022. t(11;14) was examined through interphase fluorescence in situ hybridization using bone marrow cells. RESULTS: The median age of the patients was 73 years, and 53.5% were male. The underlying diseases included symptomatic multiple myeloma, smoldering multiple myeloma, Waldenström macroglobulinemia, and monoclonal gammopathy of undetermined significance, representing 33.8%, 26.8%, 2.8%, and 36.6%, respectively. The prevalence of cyclin D1 and t(11;14) was 38.0% and 34.7%, respectively. Higher frequency of light chain paraprotein type was seen in cyclin D1-positive patients with AL than in cyclin D1-negative patients (70.4% vs 18.2%). The median overall survival (OS) of patients with AL with and without cyclin D1 expression was 18.9 months and 73.1 months, respectively (P = .019). Early death occurred in 44.4% of cyclin D1-positive patients and 31.8% of cyclin D1-negative patients. Moreover, 83.3% of cyclin D1-positive patients and 21.4% of cyclin D1-negative patients died of cardiac causes. CONCLUSIONS: Cyclin D1 immunohistochemistry accurately identified patients with t(11;14). Cyclin D1-positive patients had significantly inferior OS compared with cyclin D1-negative patients.

Antibody status following booster vaccination against SARS-CoV-2 virus in patients with haematologic malignancies.

Antibody titres in 462 patients with haematological malignancies after the second (D2) and third (D3) SARS-CoV-2 vaccine were compared with those of healthy controls (HCs). Significant decay of antibody titre was observed pre D3, but titre surged post D3. The number of seronegative patients decreased from 79 (17.1%) to 44 (9.5%) from post D2 to post D3, and patients with adequate antibody titre increased from 204 (44.2%) to 358 (77.5%). Of the patients who received B-cell-targeted therapy, 80% were seronegative and 71% remained seronegative after D3. CD19+, CD4+, CD8+ cell counts, and immunoglobulin G (IgG) levels were identified as independent predictors for adequate serologic response.

Limited efficacy of high-dose methotrexate to prevent the central nervous system relapse in patients with IVLBCL.

To evaluate the efficacy of high-dose methotrexate (HD-MTX, ≥1 g/m2) for the prevention of central nervous system (CNS) recurrence in patients with intravascular large B-cell lymphoma (IVLBCL), we reviewed 51 patients with pathologically diagnosed untreated IVLBCL. In total, there were five cases of CNS relapse (9.8%), and the 12-month CNS relapse rate was 9.2%. No statistical difference in CNS relapse rate (p = 0.86) was observed between patients with and without HD-MTX (n = 20 and 31, respectively). Furthermore, the composite endpoint defined as either CNS and/or neurolymphomatosis relapse was not significant in terms of the administration of HD-MTX (p = 0.25). No significant predictor of CNS relapse was found. In conclusion, patients with IVLBCL are at high risk of CNS recurrence; however, HD-MTX administration may not be effective for CNS recurrence prophylaxis. Key pointsThe administration of HD-MTX for patients with untreated IVLBCL may not be effective for preventing CNS relapse.

Management of lymphoma-associated chylothorax by interventional radiology and chemotherapy: a report of five cases.

Chylous effusion is associated with lymphatic obstruction or leakage in mediastinal or abdominal lymph nodes, and is a rare but troublesome complication in patients with malignant lymphomas. Although there is no standard of care, it is often treated with simultaneous chemotherapeutic and non-chemotherapeutic interventions. Here, we describe the cases of five patients with lymphoma-associated chylothorax with the aim of clarifying an effective treatment strategy. All patients achieved a partial response or better for lymphoma. All patients underwent interventional radiology (IVR) procedures, including lymphangiography (LAG) and thoracic duct embolization (TDE). Complete resolution of chylothorax was eventually achieved by IVR procedures or pleurodesis in all patients. No patients experienced serious adverse events related to LAG/TDE. Treatment of chylous effusion required months for most patients (range: 0.2-4.8 months). Our data suggest that a combination of chemotherapy and LAG/TDE is effective for refractory lymphoma-related chylous effusion.

Antibody response to COVID-19 vaccine in 130 recipients of hematopoietic stem cell transplantation.

We evaluated anti-spike protein antibody (anti-S) production in 130 hematopoietic stem cell transplant (HSCT) recipients who received the coronavirus disease-2019 vaccine. Sixty-five received allo-HSCT and 65 received auto-HSCT. Disease-specific treatments were being administered to 43.1% of allo-HSCT and 69.2% of auto-HSCT patients. Seropositivity was observed in 87.7% of allo-HSCT and 89.2% in auto-HSCT patients. Anti-S antibody production was significantly impaired in auto-HSCT patients compared with controls (178U/mL [0.4-4990.0] vs. 669 U/mL [40.3-4377.0], p < 0.001), but not in allo-HSCT patients (900 U/mL [0.4-12,893.0] vs. 860 U/mL [40.3-8988.0], P = 0.659). Clinically relevant anti-S antibody levels (> 264 U/mL) were achieved in 59.2% of patients (76.9% in allo-HSCT and 41.5% in auto-HSCT). The main factors influencing the protective level of the antibody response were the CD19 + cell count and serum immunoglobulin G levels, and these were significant in both allo-HSCT and auto-HSCT patients. Other factors included time since HSCT, complete remission status, use of immunosuppressive drugs, and levels of lymphocyte subsets including CD4, CD8 and CD56 positive cells, but these were only significant in allo-HSCT patients. Allo-HSCT patients had a relatively favorable antibody response, while auto-HSCT patients had poorer results.

Carfilzomib-induced thrombotic microangiopathy is underestimated in clinical practice: A report of five patients and literature review.

Carfilzomib (Cfz) is widely used to treat multiple myeloma. However, real-world data of the incidence of thrombotic microangiopathy (TMA) caused by Cfz is inconsistent (<1-5%). We evaluated 96 consecutive patients who received Cfz to evaluate the incidence of TMA in clinical practice. TMA developed in five patients (5.2%) who were mainly receiving high-dose Cfz (≥56 mg/m2). Based on a literature review, precaution should be taken for Cfz-induced TMA in male patients receiving high-dose Cfz irrespective of the combination therapy, Cfz administration period, and complement level. In conclusion, Cfz-induced TMA might be underestimated in clinical practice, and early intervention should be considered.

Impaired Antibody Response Following the Second Dose of the BNT162b2 Vaccine in Patients With Myeloproliferative Neoplasms Receiving Ruxolitinib.

Data on the effect of ruxolitinib on antibody response to severe acute respiratory coronavirus 2 (SARS-CoV-2) vaccination in patients with myeloproliferative neoplasms (MPN) is lacking. We prospectively evaluated anti-spike-receptor binding domain antibody (anti-S Ab) levels after the second dose of the BNT162b2 (Pfizer-BioNTech) vaccine in MPN patients. A total of 74 patients with MPN and 81 healthy controls who were vaccinated were enrolled in the study. Of the MPN patients, 27% received ruxolitinib at the time of vaccination. Notably, MPN patients receiving ruxolitinib had a 30-fold lower median anti-S Ab level than those not receiving ruxolitinib (p < 0.001). Further, the anti-S Ab levels in MPN patients not receiving ruxolitinib were significantly lower than those in healthy controls (p < 0.001). Regarding a clinical protective titre that has been shown to correlate with preventing symptomatic infection, only 10% of the MPN patients receiving ruxolitinib had the protective value. Univariate analysis revealed that ruxolitinib, myelofibrosis, and longer time from diagnosis to vaccination had a significantly negative impact on achieving the protective value (p = 0.001, 0.021, and 0.019, respectively). In subgroup analysis, lower numbers of CD3+ and CD4+ lymphocytes were significantly correlated with a lower probability of obtaining the protective value (p = 0.011 and 0.001, respectively). In conclusion, our results highlight ruxolitinib-induced impaired vaccine response and the necessity of booster immunisation in MPN patients. Moreover, T-cell mediated immunity may have an important role in the SARS-CoV-2 vaccine response in patients with MPN, though further studies are warranted.

Low clinical protective response to SARS-CoV-2 mRNA COVID-19 vaccine in patients with multiple myeloma.

We conducted a prospective, three-center, observational study in Japan to evaluate the prevalence of seropositivity and clinically protective titer after coronavirus disease 2019 vaccination in patients with plasma cell dyscrasia(PCD). Two-hundred sixty-nine patients with PCD [206 symptomatic multiple myeloma (MM)] were evaluated. Seropositivity was observed in 88.7% and a clinically protective titer in 38.3% of MM patients, both of which were significantly lower than those of healthy controls. Patients receiving anti-CD38 antibodies had much lower antibody titers, but antibody titers recovered in those who underwent a wash-out period before vaccine administration. Older age (≥65), anti-CD38 antibody administration, immunomodulatory drugs use, lymphopenia (<1000/µL), and lower polyclonal IgG (<550 mg/dL) had a negative impact for the sufficient antibody production according to multivariate analysis. Patients with clinically protective titer had a significantly higher number of CD19+ lymphocytes than those with lower antibody responses (114 vs. 35/µL, p = 0.016). Our results suggested that patients with PCD should be vaccinated, and that the ideal protocol is to temporarily interrupt anti-CD38 antibody therapy for a "wash-out" period of a few months, followed by a (booster) vaccine after the B-cells have recovery.

Antibody response to COVID-19 vaccination in patients with lymphoma.

Patients with lymphoma are at increased risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); therefore, evaluation of SARS-CoV-2 vaccination efficacy is essential. We conducted a prospective observational study to monitor the antibody response in 500 patients with lymphoma after SARS-CoV-2 vaccination. Antibody levels increased in a stepwise manner after the first and second dose of the vaccine. After completion of the two-dose series, anti-S antibody was negative in 109 patients (21.8%), and below clinically protective levels (anti-S ≥ 264 U/mL) in 236 patients (47.2%). The median anti-S titers at 0-6 months, 7-12 months, 13-24 months, and 24 months after treatment completion were 0.4 U/mL, 3.8 U/mL, 270 U/mL, and 650 U/mL, respectively. Multivariate analysis showed that receiving the vaccine < 6 months since completing treatment, white blood cell count < 5050/µL, percentage of CD19 + cells < 10%, CD4 + cells < 27%, immunoglobulin (Ig) A < 195 mg/dL, IgM < 50 mg/dL, serum soluble interleukin 2 receptor > 600 U/mL, and presence of lymphoma cells in the peripheral blood were significantly correlated with anti-S < 264 U/mL. Lymphoma patients had variably impaired antibody response to the SARS-CoV-2 vaccine. We identified various factors to predict COVID-19 vaccine effectiveness in lymphoma patients that may help tailoring possible vaccine boosters.

Depletion of CD38-positive regulatory T cells by anti-CD38 monoclonal antibodies induces a durable response to SARS-CoV-2 vaccination in patients with plasma cell dyscrasia.

This study reports the relationship between CD38+ regulatory T cells (Tregs) and messenger RNA coronavirus disease 2019 (mRNA-COVID-19) vaccination in 60 patients with plasma cell dyscrasia. Patients treated with anti-CD38 monoclonal antibodies (mAbs) had significantly lower CD38+ Tregs than those not treated (0.9 vs. 13.2/µl). Late-responders, whose antibody titres increased from weeks 4-12 after the second vaccination, had significantly lower CD38+ Treg counts than non-late-responders (2.5 vs. 10.3/µl). Antibody titres in patients with lower CD38+ Treg levels were maintained from weeks 4-12 but decreased in those with higher CD38+ Treg levels. Therefore, depletion of CD38+ Tregs by anti-CD38 mAbs may induce a durable response to mRNA-COVID-19 vaccination.

Association of loss of spleen visualization on whole-body diffusion-weighted imaging with prognosis and tumor burden in patients with multiple myeloma.

This study investigated the clinical significance of loss of spleen visualization (LSV) on whole-body diffusion-weighted imaging (WB-DWI) in patients with multiple myeloma (MM). The WB-DWI of 96 patients with newly diagnosed MM (NDMM) and 15 patients with smoldering MM (sMM) were retrospectively reviewed. LSV was observed in 56 patients with NDMM (58.3%) and 1 patient with sMM (6.7%). Patients with NDMM with LSV had a higher median infiltration of bone marrow plasma cells (80.0% vs. 50.0%, p < 0.001) and median total diffusion volume (median; 540.2 vs. 137.0 mL, p = 0.003) than patients without LSV. Patients with LSV had a lower spleen-to-spinal cord ratio (0.36 vs. 0.96, p < 0.001) and worse 2-year overall survival (OS) (84.6% vs. 100%, p = 0.032). Patients who did not recover spleen visualization during treatment had a worse prognosis, even when they obtained very good partial response (median progression-free survival: 13.2 months). Spleen histopathological findings revealed higher cellularity and diffuse myeloma cell infiltration in a patient with LSV and splenic amyloidosis without extramedullary hematopoiesis in a patient without LSV. Therefore, LSV indicates worse prognosis for patients with MM, even when the patient responds to treatment. Further studies are warranted to clarify the immunological role of spleen in MM.

[Successful treatment of refractory chylothorax associated with diffuse large B-cell lymphoma by multidisciplinary care].

Chylothorax is an intrathoracic leakage of chyle due to thoracic duct damage. Malignant lymphoma is the most common nontraumatic cause of chylothorax. In March 2019, a 74-year-old woman presented to our department with bilateral pleural effusion and mesenteric/retroperitoneal masses. She was diagnosed with diffuse large B-cell lymphoma upon performing a biopsy. In May 2019, she was hospitalized for dyspnea due to pleural effusion, and thoracentesis revealed abundant chyle. Although the tumor shrunk after chemotherapy, chylothorax improvement was poor; thus, she could not be discharged. For the management of refractory chylothorax, lymphangiography, thoracic duct embolization, and pleurodesis were performed, and the chylothorax improved immediately. However, in May 2020, right chylothorax recurred without a relapse of malignant lymphoma, which did not improve with conservative treatment. Lymphangiography was performed again; however, treatment via the lymphatic vessels was difficult. Thus, pleurodesis was performed four times, after which the chylothorax regressed. Chylothorax is often refractory. When chemotherapy for malignant lymphoma does not improve chylothorax, multidisciplinary treatment is effective.

Quantification of measurable residual disease in patients with multiple myeloma based on the IMWG response criteria.

Stringent complete response (sCR) is defined as a deeper response than complete response (CR) in multiple myeloma. Whether achieving sCR correlates with better survival remains controversial. We evaluated the outcomes in patients with intact immunoglobulin multiple myeloma (IIMM) and light chain multiple myeloma (LCMM) who achieved a very good partial response (VGPR) or better. Multicolour flow cytometry was used to assess the depth of response. LCMM patients with sCR had significantly lower measurable residual disease (MRD) levels than those with CR (median MRD: 7.9 × 10-4 vs. 5.6 × 10-5, P < 0.01). Nonetheless, no significant difference was observed in MRD levels across the responses in groups of patients with IIMM (VGPR vs. CR: 3.5 × 10-4 vs. 7.0 × 10-5, P = 0.07; CR vs. sCR: 7.0 × 10-5 vs. 5.4 × 10-5, P = 0.81. In accordance with MRD levels, the median overall survival of patients with sCR was significantly longer (sCR, CR, VGPR; not reached, 41 months, and 58 months, respectively; VGPR vs. CR, P = 0.83; CR vs. sCR, P = 0.04) in LCMM, but not in IIMM (sCR, CR, VGPR; not reached, 41 months, and not reached, respectively; VGPR vs. CR, P = 0.59; CR vs. sCR; P = 0.10). Our results show that sCR represents a deeper response that correlates with longer survival in patients with LCMM, but not IIMM.

Multiple myeloma with t(11;14)-associated immature phenotype has lower CD38 expression and higher BCL2 dependence.

CD38 expression on myeloma cells is a critical factor affecting the early response to the anti-CD38 antibody daratumumab. However, factors affecting CD38 expression in untreated multiple myeloma are not fully elucidated. In this study, we found that CD38 expression was significantly lower in myeloma patients with the translocation t(11;14)-associated immature plasma cell phenotype, and particularly in those expressing B-cell-associated genes such as PAX5 and CD79A. CD138, a representative marker of plasmacytic differentiation, was also significantly lower in these patients, suggesting that CD38 expression may be associated with the differentiation and maturation stages of myeloma cells. Furthermore, the BCL2/BCL2L1 ratio, a response marker of the BCL2 inhibitor venetoclax, was significantly higher in patients with the immature phenotype expressing B-cell-associated genes. The BCL2/BCL2L1 ratio and CD38 expression were significantly negatively correlated. We also confirmed that patients with translocation t(11;14) expressing B-cell-associated genes were indeed less sensitive to daratumumab-mediated direct cytotoxicity but highly sensitive to venetoclax treatment in ex vivo assays. Moreover, all-trans-retinoic acid, which enhances CD38 expression and induces cell differentiation in myeloma cells, reduced B-cell marker expression and the BCL2/BCL2L1 ratio in myeloma cell lines, leading to reduced efficacy of venetoclax. Venetoclax specifically induces cell death in myeloma with t(11;14), although why patients with translocation t(11;14) show BCL2 dependence is unclear. These results suggest that BCL2 dependence, as well as CD38 expression, are deeply associated with the differentiation and maturation stages of myeloma cells. This study highlights the importance of examining t(11;14) and considering cell maturity in myeloma treatment strategies.

Prognostic Impact of Metabolic Heterogeneity in Patients With Newly Diagnosed Multiple Myeloma Using 18F-FDG PET/CT.

PURPOSE: This study aimed to investigate the prognostic impact of metabolic heterogeneity (MH) in patients with multiple myeloma (MM). PATIENTS AND METHODS: We retrospectively analyzed MH with 18F-FDG PET/CT in 203 patients with newly diagnosed MM. Metabolic heterogeneity was estimated using the area under the curve of the cumulative SUV volume histogram. To evaluate MH, we selected 2 lesions: "MH-SUVmax," a lesion with SUVmax, and "MH-metabolic tumor volume (MTV)," a lesion with the largest MTV. RESULTS: Metabolic heterogeneity from an MH-SUVmax lesion showed more prognostic relevance than that from a lesion with the largest MTV. The progression-free survival (PFS) and overall survival (OS) rates were significantly lower in the high-MH-SUVmax group than in the low-MH-SUVmax group (median PFS: 25.2 vs 33.9 months; median OS: 41.6 vs 112.0 months; P = 0.004 and 0.046, respectively), whereas high MH-SUVmax retained independent prognostic power on multivariate analysis. Even among patients with high whole-body MTV, those with high MH-SUVmax tended to show poorer prognosis than those without (median PFS, 23.8 vs 30.2 months; P = 0.085). Moreover, patients with high MH-SUVmax and high-risk cytogenetic abnormalities showed dismal outcomes even with standard treatment (median PFS and OS, 10.0 and 33.3 months, respectively). CONCLUSIONS: Our results suggested that high MH-SUVmax based on pretreatment with 18F-FDG PET/CT is a novel prognostic factor for cases of MM.

Letermovir Administration to Prevent Cytomegalovirus Reactivation Is the Potential Risk of Chronic Graft-Versus-Host Disease in Patients Who Received Haploidentical Stem-Cell Transplantation With Post-Transplant Cyclophosphamide.

The prevention of chronic graft-versus-host disease (cGVHD) is important for recipients of hematopoietic stem-cell transplantation (HSCT). As one of the etiologies, the relationship between early T-cell recovery and subsequent cGVHD development has been the focus of attention. Recently, letermovir (LTV) was approved for preventing cytomegalovirus (CMV) reactivation in the early transplantation phase. Although CMV affects the immune reconstitution after HSCT, the impacts of LTV to prevent CMV reactivation on early T-cell recovery and cGVHD have not been fully investigated. We aimed to identify early T-cell recovery under LTV at day 30 in 15 and 33 recipients from matched related donors (MRDs) and haploidentical donors with post-transplant cyclophosphamide (PTCy-haplo), respectively. Early increases in the levels of total lymphocytes and HLA-DR+ activated T-cells at day 30 were observed under CMV prophylaxis by LTV only in PTCy-haplo recipients and not in MRD recipients. Moreover, PTCy-haplo recipients with LTV showed a significantly higher incidence of cGVHD, but not acute GVHD. Our observations suggest that an early increase in the levels of HLA-DR+ activated T-cells may be implicated in the development of cGVHD in patients treated with PTCy who received LTV. Further studies are warranted to validate our results and elucidate the detailed mechanisms of our new insights.