First-Line Combination with Proteasome Inhibitor-Based Treatment and Zoledronic Acid Is Effective in Reducing Later Fractures in Multiple Myeloma Irrespective of Multiple Myeloma Bone Disease at Diagnosis.

The present study provides real-world evidence on the treatment of multiple myeloma (MM) bone disease with various bisphosphonates combined for different myeloma-specific treatments as no validated data regarding the best combination treatment for bone disease associated with MM are available. We examined retrospectively 345 MM patients treated with autologous stem cell transplantation in Finland during 1996-2020. The median age of the patients was 60 years with a median follow-up time of 50 months (1-339). At diagnosis, 72.1% of the patients had myeloma-associated bone disease and 45.8% had fractures. Most patients (58.8%) received proteasome inhibitor (PI)-containing treatment at first line. MM bone disease was treated in 91.6% of the patients; 49.9% received zoledronic acid (ZA) and 29.9% pamidronate. Inferior overall survival was associated with MM bone disease at diagnosis (p = 0.005) or a fracture at diagnosis (p = 0.003). A later fracture was identified in 29% of the patients, and in those patients without MM bone disease at diagnosis later fractures were less common after ZA treatment (p = 0.049). PI-based treatment plus ZA (p = 0.019) seemed to be the best combination to prevent later fractures, even though the same patient subgroup was more likely to experience relapse (p = 0.018), and also when excluding patients with previous induction therapy without novel agents (p = 0.008). To conclude, this study suggests that the best therapy to prevent later fractures in MM might be PI-based treatment combined with ZA.

Patient's HLA Genotype Is Associated With the Risk of Central Nervous System Dissemination and Clinical Disease Presentation in Diffuse Large B-cell Lymphoma.

BACKGROUND/AIM: Central nervous system (CNS) involvement in aggressive B-cell lymphoma, either as a primary or secondary event to systemic disease, portends a poor prognosis. This study sought to identify patients at high risk for CNS relapse by analyzing their human leukocyte antigen (HLA) genotypes. PATIENTS AND METHODS: We retrospectively examined the HLA genotypes of 164 patients with systemic lymphoma, primary CNS lymphoma, and CNS relapse of systemic lymphoma. Patient records were analyzed, and HLA typing was performed by the Finnish Red Cross Blood Service. After excluding patients who received CNS prophylaxis, 131 patients were included in the final analysis. RESULTS: A strong association was found between the HLA-A*31 genotype and CNS disease (p=0.001). Additionally, various HLA genotypes were linked to lactate dehydrogenase levels, extranodal disease, International Prognostic Index score, and disease stage. CONCLUSION: The patient's genetic constitution, rather than solely disease-related factors, plays a role in the tropism of lymphoma for the CNS. If confirmed in a larger study, defining the HLA genotype of a lymphoma patient could provide valuable information for predicting CNS relapse.

Progression-free survival after front line, second line and third line in patients with follicular lymphoma treated in clinical practice.

BACKGROUND: The modern-day therapeutic landscape for follicular lymphoma (FL) includes a number of highly effective therapies. PATIENTS AND METHODS: We set out to determine progression-free survival (PFS) after front line, second line, and third line of therapy on the basis of relevant biological characteristics and therapeutic choices. Patients (n = 743, 51% females, median 60 years old) diagnosed with grade 1-2 FL between 1997 and 2016 in nine institutions were included. RESULTS: The median PFS1, PFS2, and PFS3 were 8.1 years (95% confidence interval [CI]: 7-9.3 years), 4.2 years (95% CI: 2.8-5.6 years) and 2.2 years (95% CI 1.7-2.8 years). We found longer PFS1 for (1) females, (2) younger age, (3) lower-risk follicular lymphoma international prognostic index (FLIPI), (4) standard intensity (over low intensity) regimens and (5) immunochemotherapy strategies and (6) maintenance rituximab. We found a shorter PFS2 for patients who received front-line immunochemotherapy. Older age at diagnosis correlated with a shorter PFS3. Intensity of front-line chemotherapy, maintenance, or POD24 status did not correlate with PFS2 or PFS3 in this dataset. INTERPRETATION: With current immunochemotherapy strategies, the natural course of FL is characterized by shorter-lasting remissions after each relapse. It will be interesting to see whether new therapies can alter this pattern.

Drug-induced pneumonitis risk in diffuse large B-cell/follicular lymphoma patients treated with R-CHOP-like regimen is associated with the use of granulocyte colony-stimulating growth factors.

BACKGROUND: Rituximab-based combinations are the standard of care in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). Despite being on market for over 20 years, some of the adverse effects associated with the use of rituximab are not well known. Drug-induced interstitial pneumonitis (DIP) is a potentially fatal complication of the treatment. Granulocyte colony-stimulating factors (G-CSF) are supportive agents commonly used to prevent neutropenic infections. G-CSF are reported to have pulmonary toxicity, but the risk of DIP is greater when used in combination with other potentially pulmotoxic agents. METHODS: In this retrospective study, we reported the G-CSF use and risk of DIP in 234 DLBCL patients and 87 FL patients receiving R-CHOP-type immunochemotherapy. RESULTS: In 72% of patients, the treatment included a G-CSF support. The overall incidence of treatment-induced pneumonitis was 6.9% in this patient group. All the DIP cases (n = 16) were among patients receiving G-CSF support (p = 0.03). Older age (over 60 years) and higher disease stage (Ann Arbor 3-4) also increased the risk of DIP. CONCLUSIONS: These findings suggest that the use of G-CSF increases the risk of DIP, when used in combination with rituximab-containing regimen.

Estimating the Lifetime Treatment Burden of Patients With Follicular Lymphoma: A Retrospective Study Using Real-World Multicenter Data.

PURPOSE: Although follicular lymphoma is characterized by long natural history and frequent relapses, data on the number of patients receiving subsequent therapy lines are scarce. To perform reliable health economical calculations for various treatment options, data regarding the lifetime number of therapy courses are needed. The purpose of this study was to use real-world data to create a model that could estimate the treatment burden over a 20-year period. MATERIALS AND METHODS: We performed a 20-year simulation on the basis of retrospectively obtained multicenter data of 743 patients with follicular lymphoma. The simulation was carried out in two steps: First, a competing risk model on the basis of Weibull distribution was used to simulate the state transitions from diagnosis onward and from first-line therapy onward. Then, the data were completed by imputing on the basis of the existing data. Completion of data was repeated for 1,000 times to estimate reliability. RESULTS: In 20 years, 97% (2.5-97.5 percentile range: 96%-98%), 66% (61%-70%), 34% (30%-41%), and 15% (9%-18%) of the patients received first-line, second-line, third-line, and fourth-line therapies, respectively. The median number of therapy lines received by each patient was two. CONCLUSION: Despite long remissions, approximately two thirds of the patients receive at least two lines and one-third at least three lines of therapy during their lifetime.

Previous radiotherapy improves treatment responses and causes a trend toward longer time to progression among patients with immune checkpoint inhibitor-related adverse events.

BACKGROUND: Immune-related adverse events (irAEs) are frequently encountered by patients during immune checkpoint inhibitor (ICI) treatment and are associated with better treatment outcomes. The sequencing of radiotherapy (RT) and ICIs is widely used in current clinical practice, but its effect on survival has remained unclear. METHODS: In a real-world multicenter study including 521 patients who received ICI treatment for metastatic or locally advanced cancer, RT schedules and timing, irAEs, time to progression, overall survival, and treatment responses were retrospectively reviewed. RESULTS: Patients who received previous RT and developed irAE (RT +/AE +) had the best overall response rate (ORR 44.0%). The ORR was 40.1% in the RT -/AE + group, 26.7% in the RT -/AE - group and 18.3% in the RT + /AE - group (p < 0.001). There was a significantly longer time to progression (TTP) in the RT + /AE + group compared to the RT -/AE - and RT + /AE - groups (log rank p = 0.001 and p < 0.001, respectively), but the trend toward longer TTP in the RT + /AE + group did not reach statistical significance in pairwise comparison to that in the RT -/AE + group. Preceding RT timing and intent had no statistically significant effect on TTP. In a multivariate model, ECOG = 0 and occurrence of irAEs remained independent positive prognostic factors for TTP (HR 0.737; 95% CI 0.582-0.935; p = 0.012, and HR 0.620; 95% CI 0.499-0.769; p < 0.001, respectively). CONCLUSIONS: Better ORR and a trend toward longer TTP were demonstrated for patients with RT preceding ICI treatment and development of irAEs, which suggests that RT may boost the therapeutic effect of immunotherapy in patients with metastatic cancers.

The Transcription Factor Twist1 Has a Significant Role in Mycosis Fungoides (MF) Cell Biology: An RNA Sequencing Study of 40 MF Cases.

The purpose of this RNA sequencing study was to investigate the biological mechanism underlying how the transcription factors (TFs) Twist1 and Zeb1 influence the prognosis of mycosis fungoides (MF). We used laser-captured microdissection to dissect malignant T-cells obtained from 40 skin biopsies from 40 MF patients with stage I-IV disease. Immunohistochemistry (IHC) was used to determinate the protein expression levels of Twist1 and Zeb1. Based on RNA sequencing, principal component analysis (PCA), differential expression (DE) analysis, ingenuity pathway analysis (IPA), and hub gene analysis were performed between the high and low Twist1 IHC expression cases. The DNA from 28 samples was used to analyze the TWIST1 promoter methylation level. In the PCA, Twist1 IHC expression seemed to classify cases into different groups. The DE analysis yielded 321 significant genes. In the IPA, 228 significant upstream regulators and 177 significant master regulators/causal networks were identified. In the hub gene analysis, 28 hub genes were found. The methylation level of TWIST1 promoter regions did not correlate with Twist1 protein expression. Zeb1 protein expression did not show any major correlation with global RNA expression in the PCA. Many of the observed genes and pathways associated with high Twist1 expression are known to be involved in immunoregulation, lymphocyte differentiation, and aggressive tumor biology. In conclusion, Twist1 might be an important regulator in the disease progression of MF.

Ex vivo venetoclax sensitivity testing predicts treatment response in acute myeloid leukemia.

The BCL-2 inhibitor venetoclax has revolutionized the treatment of acute myeloid leukemia (AML) in patients not benefiting from intensive chemotherapy. Nevertheless, treatment failure remains a challenge, and predictive markers are needed, particularly for relapsed or refractory AML. Ex vivo drug sensitivity testing may correlate with outcomes, but its prospective predictive value remains unexplored. Here we report the results of the first stage of the prospective phase II VenEx trial evaluating the utility and predictiveness of venetoclax sensitivity testing using different cell culture conditions and cell viability assays in patients receiving venetoclax-azacitidine. Participants with de novo AML ineligible for intensive chemotherapy, relapsed or refractory AML, or secondary AML were included. The primary endpoint was the treatment response in participants showing ex vivo sensitivity and the key secondary endpoints were the correlation of sensitivity with responses and survival. Venetoclax sensitivity testing was successful in 38/39 participants. Experimental conditions significantly influenced the predictive accuracy. Blast-specific venetoclax sensitivity measured in conditioned medium most accurately correlated with treatment outcomes; 88% of sensitive participants achieved a treatment response. The median survival was significantly longer for participants who were ex vivo-sensitive to venetoclax (14.6 months for venetoclax-sensitive patients vs. 3.5 for venetoclax-insensitive patients, P<0.001). This analysis illustrates the feasibility of integrating drug-response profiling into clinical practice and demonstrates excellent predictivity. This trial is registered with ClinicalTrials.gov identifier: NCT04267081.

Mortality among patients with low-grade follicular lymphoma: A binational retrospective analysis.

BACKGROUND: The life expectancy of patients with follicular lymphoma (FL) has improved considerably since the introduction of rituximab. This study examined the proportion of deaths from progressive lymphoma and the impact of FL on survival compared with that in the general population. METHODS: Altogether, 749 patients with grades 1 and 2 FL in 9 institutions between 1997 and 2016 were enrolled. Competing risk models were used to estimate the cumulative incidences of deaths from progressive lymphoma and from other reasons. Excess mortality was analyzed with respect to the corresponding background populations standardized for age and sex using the excess mortality model based on the penalized spline approach. RESULTS: The median follow-up duration was 69 months (range, 0-226 months). The estimated 10-year overall, disease-specific, and net survival rates were 72.4%, 86.6%, and 86.4%, respectively. The cumulative incidence of deaths from progressive lymphoma was slightly smaller than that of other causes in the study population (estimated 10-year cumulative incidences: 12.3% [95% CI, 9.6%-15.3%] and 15.4% [95% CI, 12.2%-18.8%], respectively). Excess mortality was observed for up to 10 years after diagnosis, and it slightly increased with time. CONCLUSIONS: Deaths from progressive lymphoma are nearly as common as deaths from other causes in FL patients during the rituximab era. Despite the improvements in survival, there was evidence of excess mortality resulting from FL for at least 10 years after diagnosis.

Incidence and clinicopathological features of Follicular T-cell lymphoma in Finland: a population-based immunohistochemical study.

Follicular T-cell lymphoma (FTCL) is a rare subtype of mature T-cell lymphoma. It was recently recognized as a separate lymphoma entity in the 2017 revised fourth edition of the World Health Organization classification. The main goals of the present study were to gain better knowledge of the incidence and histopathological and clinical features of FTCL in Finland. In this study, we reviewed all angioimmunoblastic T-cell (AITL) and peripheral T-cell lymphomas, not otherwise specified, from the patient records in three hospital districts in Finland over a 10-year period, to identify FTCL cases and estimate its incidence. Five patients rediagnosed with FTCL and 34 with AITL were analyzed. Hodgkin/Reed-Sternberg (HRS)-like cells were observed in 24 of the 34 AITL cases and four of the five FTCL cases. We found that the main features that differentiated FTCL from AITL were rosetting of T-cells around HRS-like cells, the absence of clear cells, follicular dendritic cell meshwork and T-cell monoclonality. Our estimated incidence of FTCL is 0.20 per 100,000 people in Finland.

Different chemokine profile between systemic and testicular diffuse large B-cell lymphoma.

Although treatment for diffuse large B-cell lymphoma (DLBCL) has taken some notable steps in the 2000s, there are still subgroups of patients suffering from high mortality and relapse rates. To further improve treatment outcomes, it is essential to discover new mechanisms of chemotherapy resistance and create new treatment approaches to overcome them. In the present study, we analyzed the expression of chemokines and their ligands in systemic and testicular DLBCL. From our biopsy sample set of 21 testicular and 28 systemic lymphomas, we were able to demonstrate chemokine profile differences and identify associations with clinical risk factors. High cytoplasmic CXCL13 expression had correlations with better treatment response, lower disease-related mortality, and limited stage. This study suggests that active CXCR5/CXCL13 signaling could overtake the CXCR4/CXCL12 axis, resulting in a better prognosis.

Female patients with follicular lymphoma have a better prognosis if primary remission lasts over 24 months.

Findings regarding the role of sex in follicular lymphoma (FL) are contradictory and the prognostic value of sex among patients with early progression of disease (POD) remains unclear. We collected real-life data from nine hospitals in Finland and Spain including 1020 FL patients to study the influence of sex on disease outcome. The median follow-up duration was 67 months (range 0-226 months). Female patients showed better progression-free survival (PFS) (hazard ratio [HR], 0.720; 95% confidence interval [CI], 0.588-0.881), disease-specific survival (DSS) (HR, 0.653; 95% CI, 0.448-0.951), and overall survival (OS) (HR, 0.653; 95% CI, 0.501-0.853) than male patients. However, there were no significant sex differences in prognosis in patients with early POD. This study strengthens the understanding that male sex is an adverse prognostic factor for FL. However, this difference does not apply to patients with early POD.

Testis-Specific Thioredoxins TXNDC2, TXNDC3, and TXNDC6 Are Expressed in Both Testicular and Systemic DLBCL and Correlate with Clinical Disease Presentation.

DLBCL is the most common type of non-Hodgkin lymphoma with a substantial group of patients suffering a poor prognosis. Therefore more specific markers are required for better understanding of disease biology and treatment. This study demonstrates that testis-specific antioxidant enzymes TXNDC2, TXNDC3, and TXNDC6 alongside oxidative stress marker 8-OHdG are expressed in both testicular and systemic DLBCL, and their presence or absence has correlations with clinical risk factors such as the number of extranodal effusion, the appearance of B-symptoms, and treatment response. Biopsy samples were collected from 28 systemic and 21 testicular male DLBCL patients. The samples were histostained with TXNDC2, TXNDC3, TXNDC6, and 8-OHdG, then graded by a hematopathologist blinded to clinical data. Immunoelectron microscopy was used as a second method to confirm the reliability of the acquired immunohistochemistry data. The absence of nuclear TXNDC2 expression in testicular DLBCL cells correlated with worse primary treatment response, cytoplasmic TXNDC3 expression in testicular and systemic DLBCL associated with lower frequency of B-symptoms, and TXNDC6 expression in cytoplasm in systemic DLBCL had a clinical significance with higher LD levels suggesting a role in the biological nature of these lymphomas. Overall, TXNDC3 cytoplasmic expression is correlated with a more positive outcome in both testicular and systemic DLBCL, while TXNDC6 cytoplasmic expression is associated with a negative outcome in systemic DLBCL.

Impact of central nervous system (CNS) prophylaxis on the incidence of CNS relapse in patients with high-risk diffuse large B cell/follicular grade 3B lymphoma.

Although overall survival in diffuse large B cell lymphomas (DLBCL) has improved, central nervous system (CNS) relapse is still a fatal complication of DLBCL. For this reason, CNS prophylaxis is recommended for patients at high risk of CNS disease. However, no consensus exists on definition of high-risk patient and optimal CNS prophylaxis. Systemic high-dose methotrexate in combination with R-CHOP has been suggested as a potential prophylactic method, since methotrexate penetrates the blood-brain barrier and achieves high concentration in the CNS. In this retrospective analysis, we report treatment outcome of 95 high-risk DLBCL/FL grade 3B patients treated with R-CHOP or its derivatives with (N = 57) or without (N = 38) CNS prophylaxis. At a median follow-up time (51 months), CNS relapses were detected in twelve patients (12.6%). Ten out of twelve (83%) of CNS events were confined to CNS system only. Median overall survival after CNS relapse was 9 months. Five-year isolated CNS relapse rates were 5% in the prophylaxis group and 26% in the group without prophylaxis. These findings suggest that high-dose methotrexate-containing prophylaxis decreases the risk of CNS failure.

Thioredoxin-1 as a biological predictive marker for selecting diffuse large B-cell lymphoma patients for etoposide-containing treatment.

OBJECTIVE: In diffuse large B-cell lymphoma (DLBCL), there is an unmet medical need to select patients who would benefit from intensified frontline treatments such as adding etoposide to an R-CHOP regimen. METHODS: The present work included a retrospective clinical analysis of two patient cohorts and an in vitro study. Primary biopsy samples from DLBCL patients treated with an etoposide-containing high-dose regimen (n = 37) and etoposide-containing frontline treatment (n = 69, R-CHOEP) were studied using immunohistochemical thioredoxin-1 (Trx1) staining. Two DLBCL cell lines expressing Trx1 were cultured, and their expression was silenced using the small interfering RNA knockdown technique. Chemoresistance was tested with doxorubicin, etoposide, vincristine, prednisolone and carboplatin. RESULTS: Thioredoxin-1 knockdown sensitised DLBCL cells to doxorubicin (P < .0001) but decreased etoposide-induced cell death (P < .00001). In DLBCL patients who received etoposide-containing frontline treatment, low cytoplasmic Trx1 expression was associated with inferior 5-year overall survival (46% vs 76%, P = .026) and disease-specific survival (68% vs 90%, P = .026). CONCLUSIONS: Strong Trx1 expression appears to increase drug resistance to doxorubicin but sensitises cells to etoposide. This implies that Trx1 expression might be the first predictive biological marker to select the patients who might benefit from adding etoposide to R-CHOP immunochemotherapy.

Peroxiredoxin 6 Serum Levels and Risk of Neutropenic Infections in Diffuse Large B-cell Lymphoma.

BACKGROUND/AIM: Diffuse large B-cell lymphoma (DLBCL) is an aggressive malignancy where antioxidant enzyme peroxiredoxin 6 (Prx6) has previously been associated with adverse outcomes. Its systemic effects in DLBCL are unknown. MATERIALS AND METHODS: This study included 53 patients with DLBCL, five patients with primary central nervous system lymphoma (PCNSL) and 20 healthy controls. The expression of Prx6 was evaluated immunohistochemically in DLBCL tissue samples and compared to its expression in blood serum. RESULTS: Prx6 expression was the highest in healthy controls, followed by DLBCL patients and PCNSL patients. Febrile neutropenic infection after the first treatment course was associated with low pre-treatment Prx6 serum levels (<14 ng/ml) (p=0.025, OR=8.615, 95% confidence interval=1.032-71.933). Serum levels of Prx6 recovered after treatment (p=0.006). CONCLUSION: Patients with low Prx6 levels might be more prone to treatment-related adverse effects through elevated levels of oxidative stress.

Incidence of solid cancer in patients with follicular lymphoma.

Introduction: Patients with follicular lymphoma (FL) have classically had a higher risk of solid cancers than the general population, but there is little data available in patients diagnosed and treated with modern day regimens.Material and methods: We conducted a retrospective multicenter study assessing the cumulative incidence of solid cancers other than nonmelanoma skin cancer in patients with FL between 1997 and 2016 and determined the standardized incidence ratio (SIR) to compare the incidence of solid cancers with that of the general populationResults: Among 1002 FL patients with 7 years of median follow-up, we found 74 solid cancers (most common breast [n = 19], lung and colon [n = 9 each]). The cumulative incidence was 3.8% at 5 years (95%CI 2.6-5.2) from the time of diagnosis and 4.4% at 5 years (95%CI 3.1-5.9%) from the time of front-line treatment. Although a comparison of all front-line strategies did not reveal differences in the risk of solid cancers, patients treated with anthracycline-based regimens appeared to have a lower incidence than those treated with bendamustine-based strategies (2.8% vs. 6.9%). However, patients receiving the former regimen were younger than the latter. On multivariable analysis, older age was correlated with the incidence of solid cancer and bendamustine-based treatment was of borderline significance. SIR for any solid cancer was 1.22 (95%CI 0.91-1.64), indicating no increased risk of solid cancer in patients with FL over that of the general population. However, on subgroup analyses, female patients treated with bendamustine-based strategies appeared to have a greater risk (SIR 3.85 [95%CI 1.45-10.27])Discussion: The incidence of solid cancer in this cohort of patients with FL was low and not greater than in the general population. However, the risk may be greater in female patients treated with bendamustine.