Sequential cellular and humoral responses after repetitive COVID-19 vaccination in patients treated with anti-CD20 antibodies.

Patients treated with anti-CD20 antibodies for haematological disorders have insufficient immune responses to mRNA COVID-19 vaccines; however, relevant sequential data are lacking. We sequentially evaluated the humoral and cellular immune responses in 22 patients who had received anti-CD20 antibodies within 12 months before the first vaccination, before and after the third and fourth vaccinations. Humoral responses improved gradually, along with the resolution of B-cell depletion. A steady increase was noted in cellular responses, regardless of the B-cell status. Our findings suggest the potential benefit of repeated vaccinations in these patients until B-cell recovery is confirmed while enhancing cellular responses.

Early prediction of cytokine release syndrome by measuring phosphate and magnesium levels following chimeric antigen receptor T cell therapy.

Introduction: Cytokine release syndrome (CRS) is a life-threatening side effect of chimeric antigen receptor T (CAR-T) cell therapy. This study investigated whether serum inorganic phosphate (IP) and magnesium (Mg) levels are predictive markers of CRS development. Methods: This single-center retrospective cohort study enrolled 16 consecutive patients with diffuse large B-cell lymphoma who had received CAR-T cell therapy. Logistic regression models with generalized estimating equations were used to evaluate whether changes in IP and Mg levels from their baseline values were associated with the development of CRS within 48 hours. Results: Decreased IP and Mg levels from baseline (per 10% change) were associated with an increased CRS incidence (adjusted odds ratio 2.18 [95% confidence interval (CI), 1.31-3.62], 3.18 [95% CI, 1.57-6.44], respectively). Conclusions: Changes in IP and Mg concentrations within 48 hours may be useful predictive markers of CRS onset.

Efficacy of letermovir in HLA-haploidentical hematopoietic transplantation with posttransplant cyclophosphamide.

BACKGROUND: Cytomegalovirus reactivation (CMV-R) is a significant complication of allogeneic hematopoietic stem cell transplantation (allo-HCT), especially in human leukocyte antigen-haploidentical transplantation (haplo-HCT) with posttransplant cyclophosphamide (PTCy). Prophylactic letermovir (LTV) prevents CMV-R in patients undergoing allo-HCT. However, evidence regarding its use in haplo-HCTs with PTCy is limited. Therefore, we aimed to investigate the efficacy of prophylactic LTV in haplo-HCT with PTCy. METHODS: We retrospectively analyzed 52 patients seropositive for CMV who underwent haplo-HCT with PTCy at our institution between January 2015 and June 2021 and compared patients who received LTV prophylaxis (LTV group: n = 29) with those who did not receive prophylaxis for CMV (control group: n = 23). The primary endpoint was the 100-day cumulative CMV-R incidence. We used Gray's test and the Fine and Gray test to compare the two groups. RESULTS: The 100-day cumulative CMV-R incidence was lower in the LTV group than in the control group (17.2% vs 81.8%, p < 0.001). Multivariate analysis revealed that prophylactic LTV reduced the 100-day cumulative CMV-R incidence (hazard ratio: 0.17, 95% confidence interval: 0.06-0.44, p < 0.001). CONCLUSIONS: Prophylactic LTV effectively prevents CMV-R in patients undergoing haplo-HCT for PTCy.

[Manufacturing results of tisagenlecleucel for acute lymphoblastic leukemia: a survey by the CAR-T cell therapy taskforce of the Japan Society of Transfusion Medicine and Cell Therapy].

The frequency of the manufacturing failure of chimeric antigen receptor (CAR)-T cell therapy in clinical practice is unknown. To clarify the current state of how likely CAR-T cell production is to succeed or fail for B-cell acute lymphoblastic leukemia (B-ALL), we analyzed cases in which the production of tisagenlecleucel was performed for patients with B-ALL at 15 facilities in Japan from October 2019 to March 2022. Total 81 patients (47 males and 34 females) were analyzed. The median age at apheresis was 13 years (1-25) with a median number of prior treatments of 4 (1-9). The numbers of patients with histories of allogeneic transplantation, inotuzumab ozogamicin, or blinatumomab treatments were 51 (63.0%), 26 (32.1%), and 37 (45.7%), respectively. The median blast percentage and CD3+ cell counts in peripheral blood were 0% (0-91.5), and 611/µl (35-4,210) at apheresis, and the median number of CD3+ cells shipped was 2.2×109 (0.5-8.3). While cases with a history of heavy prior treatment before apheresis were included, no manufacturing failures were observed. Continuing to monitor the status of manufacturing failures is necessary as the number of B-ALL cases treated with CAR-T cell therapy increases.

Risk factors for CAR-T cell manufacturing failure among DLBCL patients: A nationwide survey in Japan.

For successful chimeric antigen receptor T (CAR-T) cell therapy, CAR-T cells must be manufactured without failure caused by suboptimal expansion. In order to determine risk factors for CAR-T cell manufacturing failure, we performed a nationwide cohort study in Japan and analysed patients with diffuse large B-cell lymphoma (DLBCL) who underwent tisagenlecleucel production. We compared clinical factors between 30 cases that failed (7.4%) with those that succeeded (n = 378). Among the failures, the proportion of patients previously treated with bendamustine (43.3% vs. 14.8%; p < 0.001) was significantly higher, and their platelet counts (12.0 vs. 17.0 × 104 /µL; p = 0.01) and CD4/CD8 T-cell ratio (0.30 vs. 0.56; p < 0.01) in peripheral blood at apheresis were significantly lower than in the successful group. Multivariate analysis revealed that repeated bendamustine use with short washout periods prior to apheresis (odds ratio [OR], 5.52; p = 0.013 for ≥6 cycles with washout period of 3-24 months; OR, 57.09; p = 0.005 for ≥3 cycles with washout period of <3 months), low platelet counts (OR, 0.495 per 105 /µL; p = 0.022) or low CD4/CD8 ratios (

Trajectories of the SARS-CoV-2 RNA load in patients with hematological malignancy.

OBJECTIVES: The higher risk of prolonged viral shedding in coronavirus disease (COVID-19) patients with hematological malignancies (HM) necessitates test-based de-isolation strategies. However, evidence to establish their appropriate isolation period is insufficient. This study investigated the factors affecting prolonged viral shedding and the requisite isolation period in these patients. METHODS: We retrospectively reviewed 14 COVID-19 patients with HM between January and April 2022, who were subjected to our test-based de-isolation strategy, followed by analysis of the viral load trajectory. The viral loads of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were evaluated using the cycle threshold (Ct ) of the reverse-transcription quantitative polymerase chain reaction. The trajectories were classified according to the time-interval from COVID-19 onset to the attainment of Ct values >30. RESULTS: The median interval between onset and attainment of a Ct value >30 was 22 days. Five patients with mild or moderate COVID-19 without intense treatment histories achieved Ct values >30 within 20 days. The other nine patients needed more than 20 days, including three patients who did not meet this criterion during the observation period. CONCLUSIONS: The SARS-CoV-2 viral load trajectories in patients with HM can be stratified by treatment history for the underlying HM and severity of COVID-19.

Humoral response and safety of the BNT162b2 and mRNA-1273 COVID-19 vaccines in allogeneic hematopoietic stem cell transplant recipients: An observational study.

BACKGROUND: The effectiveness of mRNA COVID-19 vaccines and the optimal timing of vaccine administration in allogeneic hematopoietic stem cell transplantation (Allo-HSCT) recipients remains inadequately investigated. We examine the effectiveness and safety of mRNA COVID-19 vaccines in allo-HSCT recipients. METHOD: This prospective observational study included 44 allo-HSCT recipients and 38 healthy volunteers. The proportion of subjects acquiring anti-S1 IgG antibodies were considered as the primary endpoint. The occurrence of adverse events after vaccination and objective deterioration of chronic graft-versus-host disease (GVHD) were defined as secondary endpoints. In addition, we compared the geometric mean titers (GMT) of anti-S1 antibody titers in subgroups based on time interval between transplantation and vaccination. RESULTS: A humoral response to the vaccine was evident in 40 (91%) patients and all 38 healthy controls. The GMT of anti-S1 titers in patients and healthy controls were 277 (95% confidence interval [CI]: 120-643) BAU/mL and 532 (95% CI 400-708) BAU/mL, respectively. (p = 0.603). A short time interval between transplantation and vaccination (≤6 months) was associated with low anti-S1 IgG antibody titers. No serious adverse events and deterioration of chronic GVHD were observed. Only one case of new development of mild chronic GVHD was recorded. CONCLUSION: Messenger RNA COVID-19 vaccines induce humoral responses in allo-HSCT recipients and can be administered safely.

[Mitoxantrone, etoposide, and cytarabine combination therapy for acute myeloid leukemia patients failing to achieve a complete remission after induction chemotherapy: a single-center experience].

Optimal salvage chemotherapy has not been established for patients with acute myeloid leukemia (AML) who fail to attain complete remission (CR) after one course of induction chemotherapy. This retrospective study aimed to assess the efficacy and safety of an MEC (mitoxantrone, 6 mg/m2, 1-3 days; etoposide, 80 mg/m2, 1-6 days; cytarabine, 1 g/m2, 1-6 days) regimen in patients with AML who failed to attain CR after one course of induction chemotherapy. Twenty-four patients were included in this study (median age, 58 years; range, 28-79 years). After one course of MEC, 11 patients (45.8%) attained CR. Febrile neutropenia was observed in all patients, and acute infection was observed in 7 patients (29.2%). However, no therapy-related death occurred. All patients eligible for transplantation and who attained CR after MEC salvage chemotherapy underwent allogeneic hematopoietic stem cell transplantation. The MEC regimen exhibited a good response rate with tolerable adverse events. Therefore, the MEC regimen can be safely used as a salvage treatment for patients with AML who failed to attain CR after one course of induction chemotherapy.

Peripheral Blood Lymphocyte-to-Monocyte Ratio at Relapse Predicts Outcome for Patients With Relapsed or Refractory Diffuse Large B-cell Lymphoma in the Rituximab Era.

BACKGROUND: Patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) have a poor prognosis, even in the rituximab era. Several studies have reported the clinical importance of the peripheral blood lymphocyte-to-monocyte ratio (LMR) in various malignancies, including lymphoma. However, the prognostic value of the LMR in relapsed/refractory DLBCL has not been well evaluated. The purpose of the present study was to investigate whether the LMR at relapse can predict clinical outcomes for relapsed/refractory DLBCL patients treated with rituximab. PATIENTS AND METHODS: We analyzed data on 74 patients with relapsed/refractory DLBCL, who were initially treated with R-CHOP (rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone) or an R-CHOP-like regimen. RESULTS: There was a significant association between a low LMR (≤ 2.6) and shorter overall survival (OS; P < .001) and progression-free survival (PFS; P < .001) compared with the high LMR group (> 2.6). Multivariate analysis showed that LMR was an independent prognostic factor for OS (P < .001) and PFS (P < .001), as was the international prognostic index (IPI) at relapse for OS. In addition, the LMR had an incremental value for OS and PFS compared with the IPI at relapse. CONCLUSION: The LMR predicts OS and PFS outcomes in relapsed/refractory DLBCL patients treated with rituximab, and might facilitate better stratification among patients in low- and intermediate-risk IPI groups.

Utility of a simple prognostic stratification based on platelet counts and serum albumin levels in elderly patients with diffuse large B cell lymphoma.

Few studies have examined the prognostic impact of blood markers [other than the five factors in the enhanced International Prognostic Index (NCCN-IPI)] in elderly patients with diffuse large B cell lymphoma (DLBCL). We retrospectively analyzed 391 DLBCL patients receiving rituximab plus anthracycline-containing chemotherapy to examine the prognostic impact of simple blood markers. The NCCN-IPI was more accurate for discriminating prognoses than the original IPI. Multivariate analysis identified platelet count (<100,000/µl) and albumin (<3.5 g/dl) levels as significantly associated with lower overall survival (OS), independently of the NCCN-IPI. These parameters stratified patients into three risk groups: platelet-albumin (PA) score low (platelet count ≥100,000/µl, albumin ≥3.5 g/dl, n = 243); intermediate (platelet count <100,000/µl, albumin ≥3.5 g/dl or platelet count ≥100,000/µl, albumin <3.5 g/dl, n = 125); and high (platelet count <100,000/µl, albumin <3.5 g/dl, n = 23). The 5-year OS rates were 81.5, 48.6, and 20.2 %, respectively (p < 0.001). Notably, most patients with a low platelet count (n = 30) were stratified into the high-risk subgroup, suggesting that platelet count was prognostic for high-risk patients with a dismal outcome. In elderly patients (n = 291), the prognostic value of the NCCN-IPI might be diminished because the low-risk category was excluded; however, the PA score was predictive of survival: the 5-year OS rates for PA score low (n = 171), intermediate (n = 101), and high (n = 19) groups were 77.6, 47.9, and 19.0 %, respectively (p < 0.001). Platelet count and albumin levels are useful prognostic factors, and their combined use can predict survival, even in elderly patients.

[Successful treatment of an overwhelming infection with granulocyte transfusion in severe aplastic anemia patient undergoing allogeneic peripheral blood stem cell transplantation].

A 19-year-old woman complaining of fever and a sore throat was diagnosed with very severe aplastic anemia (AA) by bone marrow examination at a local hospital. Despite administration of antibiotics and granulocyte-colony stimulating factor to treat the soft tissue infection in her neck, her neutrophil count showed no increase. Because emergent allogeneic stem cell transplantation (SCT) was necessary, she was referred to our hospital. On admission, computed tomography revealed right-sided severe pharyngitis and lymphadenitis causing tracheal stenosis, and emergent intubation was required the next day. Granulocyte transfusion therapy (GTX) from related donors coupled with broad-spectrum antibiotic administration controlled the otherwise overwhelming infection. The patient received allogeneic peripheral blood SCT using a reduced-intensity conditioning regimen. After allogeneic SCT, successful engraftment was obtained. She was discharged from the hospital 59 days after allogeneic SCT. She remains alive and well, as of the latest follow up. This case clearly demonstrates that GTX is useful for controlling severe infection and enables patients with severe AA to receive allogeneic SCT safely.

Infective endocarditis caused by Scedosporium prolificans infection in a patient with acute myeloid leukemia undergoing induction chemotherapy.

Disseminated Scedosporium prolificans infection occurs mainly in immunocompromised patients. The mortality rate is high, as the fungus is resistant to most antifungal agents. Here, we present the case of a 66-year-old female with acute myeloid leukemia who developed infective endocarditis caused by S. prolificans infection during induction chemotherapy. Her 1,3-ß-D-glucan levels were elevated and computed tomography revealed bilateral sinusitis and disseminated small nodular masses within the lungs and spleen; it nonetheless took 6 days to identify S. prolificans by blood culture. The patient died of multi-organ failure despite the combined use of voriconazole and terbinafine. Autopsy revealed numerous mycotic emboli within multiple organs (caused by mitral valve vegetation) and endocarditis (caused by S. prolificans). The geographic distribution of this infection is limited to Australia, the United States, and southern Europe, particularly Spain. The first Japanese case was reported in 2011, and four cases have been reported to date, including this one. Recently, the incidence of S. prolificans-disseminated infection in immunocompromised patients has increased in Japan. Therefore, clinicians should consider S. prolificans infection as a differential diagnosis when immunocompromised patients suffer disseminated infections with elevated 1,3-ß-D-glucan levels.

The prognostic impact of absolute lymphocyte and monocyte counts at diagnosis of diffuse large B-cell lymphoma in the rituximab era.

BACKGROUND: A recent report showed that the combination of the absolute lymphocyte count (ALC) and the absolute monocyte count (AMC) at diagnosis gave a prognostic score in diffuse large B-cell lymphoma (DLBCL). However, this model requires validation in other patient cohorts. METHODS: We retrospectively evaluated the prognostic impact of the combination of the ALC and the AMC at diagnosis in a cohort of 299 DLBCL patients who were treated in the rituximab era at a single institution. RESULTS: In univariate analyses, an ALC ≤1.0 × 10(9)/l [4-year overall survival (OS) rate 47.0 vs. 79.4%; p < 0.001] and an AMC ≥0.63 × 10(9)/l (4-year OS rate 52.4 vs. 75.6%; p < 0.001) were associated with inferior OS, respectively. In multivariate analyses, an ALC ≤1.0 × 10(9)/l and an AMC ≥0.63 × 10(9)/l were significantly associated with inferior OS independently of the International Prognostic Index. Furthermore, the combination of ALC and AMC could identify patients with the dismal prognosis; the 4-year OS rates for patients with ALC ≤1.0 × 10(9)/l and AMC ≥0.63 × 10(9)/l were 18.8%. CONCLUSIONS: The combination of ALC and AMC at diagnosis may be useful for the prognostic stratification of patients with DLBCL.

The need for continuing chemotherapy for leukemic cell lysis pneumopathy in patients with acute myelomonocytic/monocytic leukemia.

Although fatal pulmonary complications frequently occur during the course of acute leukemia, a minor proportion of the complications are due to leukemia itself. Infections, drug reactions and concomitant medical conditions are the major causes of respiratory distress in leukemic patients. We treated four patients with acute myeloid leukemia complicated by leukemic cell lysis pneumopathy (LCLP). All of the patients had leukemia of monocytoid origin and their respiratory function deteriorated soon after chemotherapy initiation. Although two of the patients required mechanical ventilation, all four improved after continued chemotherapy. Our experience indicates that, in cases of LCLP, chemotherapy should be continued with maximal respiratory support.