Pooled analysis of pralatrexate single-agent studies in patients with relapsed/refractory peripheral T-cell lymphoma.

ABSTRACT: Patients with relapsed or refractory (R/R) mature natural killer cell and T-cell lymphoma have limited treatment options. To evaluate pralatrexate's performance and factors influencing its safety and efficacy in R/R peripheral T-cell lymphoma (PTCL), we performed a pooled analysis of data from 4 similarly designed, regulatory-mandated prospective clinical trials. Of 221 patients (median age, 59 years; 67.0% male) in the study population, 48.9% had PTCL not otherwise specified (PTCL-NOS), 21.3% angioimmunoblastic T-cell lymphoma, and 11.8% ALK-negative anaplastic large cell lymphoma (ALCL). Patients received pralatrexate for a median of 2.56 months (range, 0.03-24.18) and had a 40.7% objective response rate with a median duration of response of 9.1 months, progression-free survival 4.6 months, and overall survival 16.3 months. The most common treatment-related all-grade adverse events were stomatitis, thrombocytopenia, white blood cell count decrease, pyrexia, and vomiting. Subgroup exploratory analyses suggest improved efficacy with 1 prior line of chemotherapy vs 2 or ≥4 prior lines; PTCL-NOS or ALCL vs transformed mycosis fungoides; chemotherapy and transplant before pralatrexate vs chemotherapy alone or chemotherapy with other nontransplant treatments. In conclusion, these pooled analysis results further support using pralatrexate in patients with R/R PTCL. Prospective studies are needed to confirm the findings of subgroups analyses.

Glofitamab as a salvage treatment for B-cell lymphomas in the real world: A multicenter study in Taiwan.

BACKGROUND: Glofitamab is a bispecific antibody with promise for treating relapsed/refractory B-cell lymphoma according to a phase 1/2 clinical trial. This study examined its real-world effectiveness. METHODS: This was an investigator-initiated, multicenter retrospective study including 34 patients who had relapsed/refractory B-cell lymphomas after at least three prior lines of therapy and received glofitamab monotherapy in a compassionate use program in Taiwan between January 2021 and October 2022. RESULTS: At a median follow-up of 15.9 months, 56% of patients responded to glofitamab and 23% achieved complete remission. Response to the previous line of therapy significantly correlated with response to glofitamab (p = .020). Most responses were durable; only five out of the 19 responders had documented disease recurrence at the data cutoff date. The estimated progression-free survival (PFS) was 3.2 months, and the estimated 1-year PFS was 33% for the entire cohort. PFS was better for responders than nonresponders (median PFS, 16.9 vs. 1.8 months; 1-year PFS, 60% vs. 0%). Forty-three cytokine release syndrome (CRS) events were observed, three of which were grade 3; all were manageable without glofitamab discontinuation. No immune effector cell-associated neurotoxicity was reported. Among seven hepatitis B virus (HBV) carriers (six had antiviral prophylaxis) and 14 patients with remote HBV (four had antiviral prophylaxis), no HBV reactivation was observed. CONCLUSIONS: In this real-world cohort, glofitamab exhibited effectiveness comparable to trial results without excessive CRS or new safety issues. With appropriate prophylaxis, glofitamab-treated patients with chronic or remote HBV infection are unlikely to experience virus reactivation.

Sabatolimab plus hypomethylating agents in previously untreated patients with higher-risk myelodysplastic syndromes (STIMULUS-MDS1): a randomised, double-blind, placebo-controlled, phase 2 trial.

BACKGROUND: Sabatolimab is an immunotherapy targeting T-cell immunoglobulin domain and mucin domain-3 (TIM-3), an immuno-myeloid regulator expressed on immune cells and leukaemic stem cells. In this trial, we compared the efficacy and safety of sabatolimab plus hypomethylating agent with placebo plus hypomethylating agents in previously untreated patients with higher-risk myelodysplastic syndromes. METHODS: STIMULUS-MDS1 was a multicentre, randomised, double-blind, placebo-controlled, phase 2 study done at 54 investigational sites in 17 countries. Adult patients (aged ≥18 years) with intermediate-risk, high-risk, and very high-risk myelodysplastic syndromes (according to Revised International Prognostic Scoring System criteria) who had not received previous treatment were included. Patients were randomly assigned (1:1) to intravenous sabatolimab (400 mg on day 8 and 22) or placebo plus a hypomethylating agent (intravenous decitabine 20 mg/m2 on day 1-5 or intravenous or subcutaneous azacitidine 75 mg/m2 on day 1-7 or day 1-5 and day 8 and 9) every 28 days until treatment discontinuation. The two primary endpoints were complete response rate and progression-free survival, assessed in the full analysis set, which included all randomly assigned patients. Complete response was analysed, as prespecified, 7 months after the last patient was randomly assigned. All other analyses presented, including progression-free survival, were done at the final data cutoff prespecified via a protocol amendment on Sept 2, 2021. Safety was assessed in in all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03946670, and is ongoing. FINDINGS: Between July 29, 2019, and Aug 10, 2020, 127 patients were randomly assigned to sabatolimab plus a hypomethylating agent group (sabatolimab group; n=65) or placebo plus a hypomethylating agent (placebo group; n=62). The median age of participants was 73 years (IQR 69-77), of whom 86 (68%) of 127 patients were male and 77 (61%) were White. The primary endpoints were not met. Complete response (cutoff date of March 10, 2021) was achieved in 14 (22%; 95% CI 12·3-33·5) of 65 patients in the sabatolimab group vs 11 (18%; 9·2-29·5) of 62 patients in the placebo group (p=0·77). At the cutoff date of the final analysis (March 1, 2022), median follow-up for progression-free survival was 17·8 months (IQR 16·6-19·4) in the sabatolimab group and 19·2 months (17·7-22·3) in the placebo group, and the median progression-free survival was 11·1 months (95% CI 7·6-17·6) in the sabatolimab group vs 8·5 months (6·9-11·3) in the placebo group (hazard ratio 0·75 [95% CI 0·48-1·17]; p=0·1022). The most common adverse events of any grade were neutropenia (35 [56%] of 62 patients in the sabatolimab group vs 43 [68%] of 63 patients in the placebo group), thrombocytopenia (30 [48%] vs 32 [51%]), constipation (29 [47%] vs 24 [38%]), diarrhoea (27 [44%] vs 14 [22%]), anaemia (22 [35%] vs 34 [54%]), febrile neutropenia (22 [35%] vs 15 [24%]), and leukopenia (15 [24%] vs 20 [32%]). One patient developed a serious potential treatment-related immune-mediated adverse event in the sabatolimab group. There was one treatment-related death in the sabatolimab group due to pneumonitis. INTERPRETATION: The addition of sabatolimab to hypomethylating agents in this study did not result in a significant improvement in complete response rates or progression-free survival. Sabatolimab had a manageable safety in most patients with higher-risk myelodysplastic syndromes. A randomised phase 3 trial is ongoing to assess the potential benefit of sabatolimab plus azacitidine on overall survival in this setting. FUNDING: Novartis Pharmaceuticals.

Correlation of low numbers of intratumoral FOXP3+ cells with worse progression-free survival in angioimmunoblastic T cell lymphoma.

AIMS: Angioimmunoblastic T cell lymphoma (AITL) is a T cell lymphoma with aberrant immune activity. It is characterised by inflammatory and immune reactions. However, the impact of regulatory T (Treg) cells on AITL remains unclear. METHODS: We retrospectively collected 46 AITL cases and performed immunohistochemical analysis of forkhead box P3 (FOXP3) expression. The number of immunostained FOXP3 cells was determined using a digital pathology system with whole-slide imaging. The average number of FOXP3+ cells per high-power field (HPF) was determined by randomly counting 20 HPFs. AITL cases were categorised into high-expression and low-expression groups based on the median count of FOXP3+ cells in all analysed samples. The relationship between FOXP3 expression and clinicopathological features was assessed. RESULTS: Among the studied patients, 14 (30.4%) were females and 32 (69.6%) were males, and the median age at diagnosis was 64.1 years. The median expression of FOXP3 was 84.9 positive cells/HPF. FOXP3 expression negatively correlated with Epstein-Barr virus-encoded small RNA positivity in tumour (p=0.041). The patients with low FOXP3 expression presented with aggressive clinical behaviour, including advance-staged diseases (p=0.043), splenomegaly (p=0.008), B symptoms (p=0.019) and extranodal involvement (p=0.019). The neutrophil-to-lymphocyte ratio was higher in the patients with low FOXP3 expression, compared with those with high FOXP3 expression. Low FOXP3 expression had an adverse effect on progression-free survival (PFS, p=0.033), and increased the risk of recurrence 2.320-fold (HR 2.320 (95% CI 1.109 to 4.856); p=0.025). CONCLUSIONS: Patients with AITL with low FOXP3 expression tend to have aggressive clinical presentation and shortened PFS. These findings may help with risk stratification and determination of new treatment strategy.

Combination of Sarcopenia and Anemia Predicts Worse Outcome in Elderly Patients With Diffuse Large B-Cell Lymphoma.

BACKGROUND/AIM: In diffuse large B-cell lymphoma (DLBCL), sarcopenia is associated with increased side-effects of chemotherapy and poor survival, especially in elderly patients. Anemia, a complex condition resulting from cancer itself and inflammation, might have a correlation with loss of muscle mass and might also indicate a worse outcome. In this study, we aimed to investigate the association of the skeletal muscle index (SMI) at the third lumbar vertebra (L3) with hemoglobin (Hb) levels and its predictive value for the outcome of DLBCL. PATIENTS AND METHODS: The study included patients, aged 70 or older, newly diagnosed with DLBCL who received immunochemotherapy. Sex-specific L3-SMI was measured by computed tomography, and Hb levels before treatment were recorded. The Kaplan-Meier method and Cox regression model were used to analyze survival and prognostic factors. RESULTS: Anemia was correlated with a low SMI. The presence of either low L3-SMI or anemia (Hb <10.5 g/l) indicated a poor prognosis for both progression-free and overall survival. A novel score combining L3-SMI, and Hb and lactate dehydrogenase levels as independent predictive factors was proposed for treatment response, progression-free and overall survival after adjusting for International Prognostic Index. CONCLUSION: This study highlights the importance of sarcopenia and anemia in patients with DLBCL, particularly in the elderly population. The proposed novel score combining L3-SMI, Hb, and lactate dehydrogenase may provide additional prognostic information for patients with DLBCL, aiding in treatment decisions and management.

Mutation-Driven S100A8 Overexpression Confers Aberrant Phenotypes in Type 1 CALR-Mutated MPN.

Numerous pathogenic CALR exon 9 mutations have been identified in myeloproliferative neoplasms (MPN), with type 1 (52bp deletion; CALRDEL) and type 2 (5bp insertion; CALRINS) being the most prevalent. Despite the universal pathobiology of MPN driven by various CALR mutants, it is unclear why different CALR mutations result in diverse clinical phenotypes. Through RNA sequencing followed by validation at the protein and mRNA levels, we found that S100A8 was specifically enriched in CALRDEL but not in CALRINS MPN-model cells. The expression of S100a8 could be regulated by STAT3 based on luciferase reporter assay complemented with inhibitor treatment. Pyrosequencing demonstrated relative hypomethylation in two CpG sites within the potential pSTAT3-targeting S100a8 promoter region in CALRDEL cells as compared to CALRINS cells, suggesting that distinct epigenetic alteration could factor into the divergent S100A8 levels in these cells. The functional analysis confirmed that S100A8 non-redundantly contributed to accelerated cellular proliferation and reduced apoptosis in CALRDEL cells. Clinical validation showed significantly enhanced S100A8 expression in CALRDEL-mutated MPN patients compared to CALRINS-mutated cases, and thrombocytosis was less prominent in those with S100A8 upregulation. This study provides indispensable insights into how different CALR mutations discrepantly drive the expression of specific genes that contributes to unique phenotypes in MPN.

Children with chronic myeloid leukaemia treated with front-line imatinib have a slower molecular response and comparable survival compared with adults: a multicenter experience in Taiwan.

BACKGROUND: The direct comparison of molecular responses of front-line imatinib (IM) monitored at the same laboratory between children and adults with chronic phase (CP) of chronic myeloid leukaemia (CML) had not been reported. In this multicenter study, we compared the landmark molecular responses and outcomes of paediatric and adult CML-CP cohorts treated with front-line IM in whom the BCR::ABL1 transcript levels were monitored at the same accredited laboratory in Taiwan. METHODS: Between June 2004 and July 2020, 55 newly diagnosed paediatric and 782 adult CML-CP patients, with molecular diagnosis and monitoring at the same reference laboratory in Taiwan, were enrolled. The criteria of 2020 European LeukemiaNet were applied to evaluate the molecular responses. RESULTS: By year 5, the cumulative incidences of IS <1%, MMR, MR4.0 and MR4.5 of paediatric patients were all significantly lower than those of adult patients (58 vs 75%, 48 vs 66%, 25 vs 44%, 16 vs 34%, respectively). The 10-year progression-free survival (PFS) (90%) and overall survival (OS) (94%) of paediatric patients did not differ from those (92%) of adult patients. CONCLUSIONS: We demonstrated the paediatric cohort had slower molecular responses to front-line IM and similar outcomes in 10-year PFS and OS in real-world practice.

Flow Cytometry Analysis Reveals a Wide Cytologic and Immunophenotypic Spectrum of Peripheral B Lymphocytes in Angioimmunoblastic T-Cell Lymphoma.

INTRODUCTION: Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive T-cell lymphoma commonly associated with B-cell dysregulation. Correlations involving B-cell dysregulation and clinicopathological features remain unclear. METHODS: We prospectively collected blood samples from 11 AITL patients and 17 healthy controls. The percentages of B-cell subpopulations and lymphocytes with IL-21 production were assessed using flow cytometry. Peripheral blood lymphocyte morphology was evaluated microscopically. RESULTS: Six of 11 (54.5%) patients presented with polyclonal hypergammaglobulinemia. Three of 11 (27.3%) tumor biopsies showed monoclonal immunoglobulin gene rearrangement. The patients exhibited significantly lower levels of naive (p < 0.001) and class-switched (p < 0.001) B cells than controls. The percentages of IgD-CD27- B cells (p = 0.007) and antibody-secreting cells (ASCs) (p = 0.001) were increased. Blood smears revealed atypical lymphocytes and immature plasma cells with morphological diversity. In comparison to normal controls, IL-21 production significantly increased in CD4+ (p < 0.001) and CD8+ (p = 0.020) T cells. B-cell clonality, RHOA G17V mutation, and the presence of sheets of clear cells and immature/mature plasma cells in lymph nodes were significantly associated with percentages of class-switched B cells and ASCs. The patients with circulating EBV DNA had a lower percentage of naive B cells (p = 0.009). CONCLUSIONS: Our results demonstrated a wide spectrum of peripheral B-cell morphologies and immunophenotypes of peripheral B cells in AITL. These findings correspond to dysregulated B-cell immunity and heterogeneous clinicopathological features.

Oral Chemotherapy Application in Elderly Patients With Diffuse Large B-Cell Lymphoma: An Alternative Regimen in Retrospective Analysis.

Background: A combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is considered the standard treatment for diffuse large B-cell lymphoma (DLBCL). However, no standard treatment has been established for older patients (age ≥ 75 years). This study retrospectively analyzed different treatment strategies in older patients with DLBCL with different chemotherapy regimens and compared the survival rate of patients using oral or intravenous form cyclophosphamide and etoposide in a single center. Methods: We reviewed the records of older patients with DLBCL, aged ≥ 75 years, from January 2010 to August 2019. The different treatment combinations, clinical characteristics, response rates, and toxicity profiles were analyzed. The median overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier (KM) method. Cox regression model was used to identify the risk factors. Results: Eighty-four patients were included. One-quarter of the patients received cytoreduction treatment because of their poor medical condition at the time of diagnosis. Twenty-six percent of the patients were aged ≥ 85 at the time of diagnosis and 46.7% completed the treatment course. Patients receiving non-anthracycline-containing (non-ACR) treatment had worse Charlson comorbidity index, worse PFS, lower body mass index, or were older. The mean anthracycline accumulative dose in the anthracycline-containing (ACR) group was 134 mg/m2. The median OS was 17.2 months and median PFS was 7.7 months. The PFS of R-CHOP is better than R-mini-CHOP and R-CVOP without statistical significance, but OS of R-CHOP is not better than the other regimens. Conclusion: The toxicity, efficacy, and KM curve for OS and PFS in the non-ACR group were lower compared to ACR group, without statistical significance. R-CVOP had similar OS with R-mini-CHOP in our study. The result does not mean etoposide could totally substitute for anthracycline, but etoposide did have lower early progression rate (12.5%), and it may be an option for frail patients with comorbidity. Oral form cyclophosphamide and etoposide could be considered as a substitute for intravenous administration because of the similar effect and toxic profile.

Comparison of molecular responses and outcomes between BCR::ABL1 e14a2 and e13a2 transcripts in chronic myeloid leukemia.

Several studies have compared the molecular responses between e14a2 and e13a2 BCR::ABL1 transcripts in chronic myeloid leukemia (CML) patients treated with front-line imatinib, but there were very limited studies on nilotinib or dasatinib-treated patients. We retrospectively analyzed the molecular responses in 1124 CML patients with the e14a2 or e13a2 transcript receiving front-line imatinib, nilotinib or dasatinib treatment. Patients with the e14a2 transcript had higher optimal response rates than those with the e13a2 transcript at 12 months in the imatinib-treated group, and 6 and 12 months in the nilotinib-treated group. The optimal response rates were not significantly different between the two transcripts in the dasatinib-treated group at landmark molecular responses. With a median follow-up time of 48.4 months, higher cumulative incidences of BCR::ABL1 International Scale ≤1% and major molecular response were observed in patients with the e14a2 rather than the e13a2 transcript receiving front-line imatinib or nilotinib treatment, but not in dasatinib-treated patients. The progression-free survival and overall survival did not differ between the two transcripts in all three treatment groups. In view of the speed and depth of molecular responses, BCR::ABL1 transcript subtypes might provide helpful information in selecting a front-line tyrosine kinase inhibitor for individual young patients with future potential treatment-free remission.

Isatuximab-Pomalidomide-Dexamethasone Versus Pomalidomide-Dexamethasone in East Asian Patients With Relapsed/Refractory Multiple Myeloma: ICARIA-MM Subgroup Analysis.

BACKGROUND: In the pivotal phase III, randomized, multicenter ICARIA-MM study (NCT02990338), isatuximab plus pomalidomide and dexamethasone (Isa-Pd) improved progression-free survival and overall response rate versus pomalidomide and dexamethasone (Pd) in the overall population of patients with relapsed/refractory multiple myeloma. PATIENTS AND METHODS: In this predefined subgroup analysis, efficacy, and safety between East Asian patients and the overall population were assessed. RESULTS: In total, 36 East Asian patients were included (Japanese, n = 13; Korean, n = 9; Taiwanese, n = 14). At a median follow-up of 11.6 months, median progression-free survival was not reached (95% confidence interval [CI] 5.80-not calculable) in the Isa-Pd arm and was 7.9 months (95% CI 2.90-not calculable) in the Pd arm. The hazard ratio for the between-group difference was 0.52 (95% CI 0.19-1.39), which was similar to the overall population (hazard ratio, 0.60; 95% CI 0.44-0.82). No new safety signals were observed, except that a higher proportion of patients in the East Asian population experienced Grade ≥ 3 neutropenia compared with the overall population. CONCLUSION: These results confirm the efficacy of Isa-Pd in East Asian patients with relapsed/refractory multiple myeloma, and the related safety data are consistent with those observed in the overall population and are manageable.

Investigation of the incidence trend of follicular lymphoma from 2008 to 2017 in Taiwan and the United States using population-based data.

BACKGROUND: The incidence of follicular lymphoma (FL) in Taiwan has not been well investigated since its inclusion as a histological subtype in the Taiwan Cancer Registry in 2008. The purpose of this study was to describe the incidence patterns of FL in Taiwan and compare the trends with those in other racial groups in the United States. MATERIALS AND METHODS: We conducted an epidemiological study using population-based data from the Taiwan Cancer Registry, Ministry of Health and Welfare, and the 18 Surveillance, Epidemiology, and End Results (SEER) registries to evaluate the FL incidence from 2008 to 2017. We calculated the annual percent change (APC) to describe the trends in the incidence of FL in subpopulations defined by race and sex over time. RESULTS: The annual age-adjusted incidence rate of FL in Taiwan increased significantly from 0.59 per 100,000 persons in 2008 to 0.82 per 100,000 persons in 2017, with an APC of 3.2. By contrast, the incidence rate in whites in the United States during the same period decreased from 3.42 to 2.74 per 100,000 persons, with an APC of -2.1. We found no significant change for the blacks (APC, -1.5%), Hispanics (APC, -0.7%), and Asians or Pacific Islanders (APC, +0.7%). The temporal trend was similar between the males and females. The relative frequency of FL among the incident non-Hodgkin lymphoma (NHL) cases also increased significantly in Taiwan from 7.64% in 2008 to 11.11% in 2017 (APC = 3.8). The relative frequency of FL among the incident NHL cases in the whites decreased from 2008 to 2012 (APC, -3.8%) and then stabilized after 2012 (APC, -0.2%). By contrast, little change in relative frequency of FL among the incident NHL cases was observed in the blacks, Hispanics, and APIs between 2008 and 2017. CONCLUSION: We found increases in the incidence of FL and the relative frequency of FL among the incident NHL cases in both males and females in Taiwan from 2008 to 2017. The FL incidence rates were unchanged for all races and sex groups in the United States, except for the decreases in the whites.

The Cost-Effectiveness Analysis of Transplant-Ineligible Myeloma Patients with Bortezomib plus Thalidomide plus Dexamethasone (VTD) or Bortezomib plus Melphalan plus Prednisolone (VMP) Treatment in Southern Taiwan.

BACKGROUND: This study aimed to evaluate the cost-effectiveness of treating transplant-ineligible myeloma patients with either a bortezomib plus thalidomide plus dexamethasone (VTD) or a bortezomib plus melphalan plus prednisolone (VMP) treatment in Taiwan. METHODS: Newly diagnosed, transplant-ineligible myeloma patients with VTD or VMP therapy were enrolled from two medical centers in southern Taiwan. Quality-adjusted life years (QALYs) were used as the measurement unit of the effectiveness evaluation, and the incremental cost-effectiveness ratio (ICER) was used for comparison between the two groups. A net monetary benefit approach and cost-effectiveness acceptability curve were also used for the cost-effectiveness assessment. A one-way sensitivity analysis was used to check the impact of different parameters. In total, 77 patients were enrolled in the study with 43 patients in the VTD group and 34 patients in the VMP group. Clinical presentations were similar without significant difference, except the VTD group had a higher survival rate (p = 0.029). Comparisons of the two groups over an eight-month time horizon revealed a significant lower mean of direct medical costs in the VTD group than in the VMP group (p < 0.001), and a significantly higher average QALY was gained (p < 0.001). CONCLUSIONS: The study demonstrated the greater clinical benefit and cost-effectiveness of VTD compared to VMP therapy in transplant-ineligible, newly diagnosed myeloma patients.

Role of quantitative hepatitis B surface antibodies in preventing hepatitis B virus-related hepatitis in patients treated with rituximab.

Hepatitis B virus (HBV) reactivation is a well-known complication after rituximab-based chemotherapy in patients with B cell lymphoma (BCL) who have resolved HBV infection. This retrospective cohort study used electronic medical records from the Kaohsiung Chang Gung Memorial Hospital. There were 128 patients with BCL and resolved HBV infection treated with 1st-line rituximab-containing therapy from 2008 to 2013. No patient received antiviral prophylaxis. Patients with high pretreatment hepatitis B surface antibody (anti-HBs titer ≥100 mIU/mL), had significantly less HBV reactivation (2.0%, 1/49) than patients with low (10-100 mIU/mL, 10.8%, 4/37) or negative anti-HBs (<10 mIU/mL, 23.8%, 10/42) (p = 0.001). No patient in the high group vs. 1 (2.7%) low group vs. 6 (14.3%) negative group developed HBV-related hepatitis (p = 0.002). Patients with high pretreatment anti-HBs have a low risk of HBV-related complications and may not require antiviral prophylaxis. We propose an algorithm for the management of HBV reactivation risk in BCL.

Differential impacts of hemolysis on coagulation parameters of blood samples: A STROBE-compliant article.

ABSTRACT: This study aimed at investigating the impact of hemolysis on different coagulation parameters.A total of 216 venous blood samples without visible hemolysis were collected from adult patients at a tertiary referral center over six months. The plasma obtained was quantified for six coagulation parameters including prothrombin time, activated partial thromboplastin time, fibrinogen, D-dimer, antithrombin III, and protein C. The rest of the plasma from each blood sample was aliquoted into three tubes, each containing 1 mL of plasma with three different volumes of cell-free hemoglobin (i.e., 2, 4, 8 µL) from lysed RBCs to create simulated hemolyzed blood samples with hemoglobin concentration of approximately 0.1, 0.2, and 0.4 g/dL to mimic mild (1+), moderate (2+), and severe (3+) hemolysis, respectively, before repeating the coagulation tests to determine possible correlation between the simulated degree of hemolysis and the changes in test results of the coagulation parameters.Spearman correlation analysis showed significant decreases in the values of activated partial thromboplastin time, fibrinogen, D-dimer, and protein C values with an increasing degree of simulated hemolysis (all P < .01). Comparison of the percentage bias of biological variance showed significant positive associations of cell-free hemoglobin concentrations with the percentage bias of D-dimer and protein C. However, only the former was still within the range of biological variance under condition of simulated hemolysis. Besides, the presence of cell-free hemoglobin regardless of concentration had a notable impact on the percentage bias of activated partial thromboplastin time, whereas the influence was non-significant for prothrombin time, fibrinogen, and antithrombin III.The results showed different impacts of simulated hemolysis on six coagulation parameters, highlighting the dependence of clinical reliability on the coagulation parameter to be investigated in hemolytic blood samples.

Subgroup analysis of ICARIA-MM study in relapsed/refractory multiple myeloma patients with high-risk cytogenetics.

Treatment benefit in multiple myeloma (MM) patients with high-risk cytogenetics remains suboptimal. The phase 3 ICARIA-MM trial (NCT02990338) showed that isatuximab plus pomalidomide-dexamethasone prolongs median progression-free survival (mPFS) in patients with relapsed/refractory MM (RRMM). This subgroup analysis of ICARIA-MM compared the benefit of isatuximab in high-risk [defined by the presence of del(17p), t(4;14) or t(14;16)] versus standard-risk patients. The efficacy of isatuximab in patients with gain(1q21) abnormality was also assessed in a retrospective subgroup analysis. In ICARIA-MM, 307 patients received isatuximab-pomalidomide-dexamethasone (n = 154) or pomalidomide-dexamethasone (n = 153). Isatuximab (10 mg/kg intravenously) was given weekly in the first 28-day cycle, and every other week thereafter. Standard pomalidomide-dexamethasone doses were given. Isatuximab-pomalidomide-dexamethasone improved mPFS (7·5 vs 3·7 months; HR, 0·66; 95% CI, 0·33-1·28) and overall response rate (ORR, 50·0% vs 16·7%) in high-risk patients. In patients with isolated gain(1q21), isatuximab addition improved mPFS (11·2 vs 4·6 months; HR, 0·50; 95% CI, 0·28-0·88) and ORR (53·6% vs 27·6%). More grade ≥3 adverse events occurred in high-risk patients receiving isatuximab (95·7%) versus the control group (67·6%); however, isatuximab did not increase events leading to discontinuation or treatment-related mortality. Isatuximab-pomalidomide-dexamethasone provides a consistent benefit over pomalidomide-dexamethasone treatment in RRMM patients regardless of cytogenetic risk.

A comprehensive retrospective cohort study of the journey of B-cell lymphoma in Taiwan.

Complete disease journey and risk factors for poor outcomes are needed to facilitate effectiveness evaluations of new therapies and clinical decision-making in B-cell Non-Hodgkin lymphoma (B-NHL), particularly in Asia where such data are lacking. This retrospective cohort study used electronic medical records from a regional medical centre in southern Taiwan to follow-up 441 patients newly diagnosed with common B-NHL subtypes: Diffuse Large B-cell Lymphoma (DLBCL), Follicular Lymphoma (FL), Chronic Lymphocytic Leukaemia/Small Lymphocytic Lymphoma (CLL/SLL), Marginal Zone Lymphoma (MZL), Mantle Cell Lymphoma (MCL), and Waldenström macroglobulinemia (WM), between 01-Jan-2008 and 31-Dec-2013, until 31-Dec-2017. Treatment pathways were modelled using a Markov approach. Stage III/IV disease at diagnosis was frequent for patients with DLBCL, FL, MCL and WM. Hepatitis B surface antigen/hepatitis C virus seropositivity was 18.6%/12.3%. Clinical responses to 1st-line treatment were observed in 76.0% (DLBCL), 87.3% (FL), 86.0% (MZL), 60.0% (MCL), and 42.9% (WM) of patients. For DLBCL, disease control was achieved by ~ 50% after 1st-line, ~ 24% after 2nd-line, ~ 17% after 3rd-line. Patients with Stage III/IV DLBCL or age > 65 years at diagnosis had lower rates of active treatment, poorer disease control and higher mortality than patients with early stage disease or age ≤ 65 years. Disease flare < 6 months after 1st-line treatment was significantly associated with mortality. Despite good clinical response rates for some sub-types, survival remains poor. New treatments are needed to improve the outcome of B-NHL.

Copanlisib plus rituximab versus placebo plus rituximab in patients with relapsed indolent non-Hodgkin lymphoma (CHRONOS-3): a double-blind, randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Copanlisib, an intravenous pan-class I PI3K inhibitor, showed efficacy and safety as monotherapy in patients with relapsed or refractory indolent non-Hodgkin lymphoma who had received at least two therapies. The CHRONOS-3 study aimed to assess the efficacy and safety of copanlisib plus rituximab in patients with relapsed indolent non-Hodgkin lymphoma. METHODS: CHRONOS-3 was a multicentre, double-blind, randomised, placebo-controlled, phase 3 study in 186 academic medical centres across Asia, Australia, Europe, New Zealand, North America, Russia, South Africa, and South America. Patients aged 18 years and older with an Eastern Cooperative Oncology Group performance status of no more than 2 and histologically confirmed CD20-positive indolent B-cell lymphoma relapsed after the last anti-CD20 monoclonal antibody-containing therapy and progression-free and treatment-free for at least 12 months, or at least 6 months for patients unwilling or unfit to receive chemotherapy, were randomly assigned (2:1) with an interactive voice-web response system via block randomisation (block size of six) to copanlisib (60 mg given as a 1-h intravenous infusion on an intermittent schedule on days 1, 8, and 15 [28-day cycle]) plus rituximab (375 mg/m2 given intravenously weekly on days 1, 8, 15, and 22 during cycle 1 and day 1 of cycles 3, 5, 7, and 9) or placebo plus rituximab, stratified on the basis of histology, progression-free and treatment-free interval, presence of bulky disease, and previous treatment with PI3K inhibitors. The primary outcome was progression-free survival in the full analysis set (all randomised patients) by masked central review. Safety was assessed in all patients who received at least one dose of any study drug. This study is registered with ClinicalTrials.gov, NCT02367040 and is ongoing. FINDINGS: Between Aug 3, 2015, and Dec 17, 2019, 652 patients were screened for eligibility. 307 of 458 patients were randomly assigned to copanlisib plus rituximab and 151 patients were randomly assigned to placebo plus rituximab. With a median follow-up of 19·2 months (IQR 7·4-28·8) and 205 total events, copanlisib plus rituximab showed a statistically and clinically significant improvement in progression-free survival versus placebo plus rituximab; median progression-free survival 21·5 months (95% CI 17·8-33·0) versus 13·8 months (10·2-17·5; hazard ratio 0·52 [95% CI 0·39-0·69]; p<0·0001). The most common grade 3-4 adverse events were hyperglycaemia (173 [56%] of 307 patients in the copanlisib plus rituximab group vs 12 [8%] of 146 in the placebo plus rituximab group) and hypertension (122 [40%] vs 13 [9%]). Serious treatment-emergent adverse events were reported in 145 (47%) of 307 patients receiving copanlisib plus rituximab and 27 (18%) of 146 patients receiving placebo plus rituximab. One (<1%) drug-related death (pneumonitis) occurred in the copanlisib plus rituximab group and none occurred in the placebo plus rituximab group. INTERPRETATION: Copanlisib plus rituximab improved progression-free survival in patients with relapsed indolent non-Hodgkin lymphoma compared with placebo plus rituximab. To our knowledge, copanlisib is the first PI3K inhibitor to be safely combined with rituximab and the first to show broad and superior efficacy in combination with rituximab in patients with relapsed indolent non-Hodgkin lymphoma. FUNDING: Bayer.

The status of jaw lesions and medication-related osteonecrosis of jaw in patients with multiple myeloma.

BACKGROUND/PURPOSE: Myeloma jaw lesions are not uncommon. The study aimed to investigate the status of jaw lesions and medication-related osteonecrosis of jaw (MRONJ) in multiple myeloma (MM) patients. METHODS: One hundred and twenty-two consecutive newly-diagnosed MM patients seeking dental care at a hospital of southern Taiwan was examined according to jaw lesions with complete follow-up data. RESULTS: Median age of the patients was 67.8 years, and 88.5% of patients were of DS stage III and 41.0% were of ISS stage III at diagnosis. Median survival was 37.9 months for 43 (35.2%) patients with jaw lesions and 57.4 months for 79 patients without jaw lesions. 1-year, 5-year and >7-year overall survival rates for patients with jaw lesions versus patients without jaw lesions were 94.9%, 67.2%, 56.7% vs 83.7%, 51.8%, 26.8% respectively. Patients with jaw lesions had the worse survival (P = 0.03). Neither age nor stage affected survival. Jaw lesions involved the mandible more often than the maxilla and stopped progressing during remission, but did not repair. Jaw lesions were the first evidence or recurrent sign of MM in six (4.9%) patients. Long-term monthly antiresorptive therapy changed the radiographic patterns of jawbones and induced MRONJ developing in 16.7% (8/48) of patients. Five (62.5%) MRONJ sites spontaneously occurred without local risk factors. CONCLUSION: Nearly one-third of MM patients develop osteolytic jaw lesions that seem to be associated with poorer survival. Jaw lesion is an independent prognostic predictor of survival in myeloma. Antiresorptive drugs at less frequent dosing regimen are crucial to minimize spontaneous MRONJ.