Methotrexate-induced subacute myelopathy: a serious but treatable complication.

Subacute myelopathy is a rare but serious complication of methotrexate (MTX) that may cause paraplegia. Although its underlying mechanisms have not been fully elucidated, homocysteine is thought to play a role in the pathogenesis of this adverse effect. Herein, we report the case of a 34-years old female patient with diffuse large B-cell lymphoma who developed progressive paraplegia accompanied by dysfunctional bladder and bowel movements after treatment with a modified CODOX-M/IVAC regimen, including high-dose intravenous MTX and intrathecal (IT-) MTX. Neurological symptoms gradually improved to almost normal levels within 4.5 months of onset following treatment with a combination of S-adenosylmethionine, methionine, cyanocobalamin, and folate. During chemotherapy, including high-dose MTX and IT-MTX for hematological malignancies, MTX-induced subacute neuronal damage should be carefully evaluated, and appropriate treatment should be initiated as early as possible.

A Prospective Study of Preemptive Tenofovir Disoproxil Fumarate Therapy in HBsAg-Positive Patients With Diffuse Large B-Cell Lymphoma Receiving Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone.

INTRODUCTION: This prospective study aimed to investigate the efficacy and safety of preemptive antiviral therapy with tenofovir disoproxil fumarate (TDF) for HBsAg-positive patients with newly diagnosed diffuse large B-cell lymphoma receiving rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy. METHODS: We enrolled 73 patients from 20 institutions. The primary end point was the absolute risk of hepatitis B virus (HBV)-related hepatitis during preemptive TDF therapy and for 24 weeks after withdrawal from TDF. Hepatitis was defined as a more than 3-fold increase in serum alanine aminotransferase from baseline or an alanine aminotransferase level of ≥100 U/L. HBV-related hepatitis was defined as hepatitis with an increase in serum HBV-DNA to >10 times that of the pre-exacerbation baseline or an absolute increase of ≥20,000 IU/mL compared with the baseline. RESULTS: No patient developed HBV reactivation or HBV-related hepatitis during preemptive antiviral therapy (until 48 weeks after completion of R-CHOP chemotherapy) with TDF. All adverse events were grade 1 or 2. HBV reactivation was reported in 17 (23.3%) patients. All HBV reactivation was developed at a median of 90 days after withdrawal from TDF (range, 37-214 days). Six (8.2%) patients developed HBV-related hepatitis at a median of 88 days after withdrawal from TDF (range, 37-183 days). DISCUSSION: Preemptive TDF therapy in HBsAg-positive patients with diffuse large B-cell lymphoma receiving R-CHOP chemotherapy was safe and effective for preventing HBV-related hepatitis. However, a long-term maintenance strategy of preemptive TDF therapy should be recommended because of the relatively high rate of HBV-related hepatitis after withdrawal from TDF ( ClinicalTrials.gov ID: NCT02354846).

The efficacy and cardiac toxicity of different-dose pegylated liposomal doxorubicin in elderly patients with diffuse large B lymphoma.

OBJECTIVES: In order to explore the impact of pegylated liposomal doxorubicin (PLD) dose intensity on survival outcomes of newly diagnosed elderly patients with diffuse large B-cell lymphoma (DLBCL), we performed a retrospective study to compare the efficacy and adverse effects of RCEOP (70 mg/m2 ), RCdOP (20-30 mg/m2 ) and RCDOP (30-45 mg/m2 ). The optimal PLD dose of patients with different clinical characteristics of subgroups was explored to provide a clue for the selection of clinical PLD dose. METHODS: A total of 335 DLBCL patients (60-85 years old) who were newly diagnosed and completed at least four cycles of RCE(D)OP were selected. The patients were mainly divided into RCEOP (126 cases) (epirubicin 70 mg/m2 ), RCdOP (151 cases) (PLD 20-30 mg/m2 ) and RCdOP (58 cases) (PLD 30-45 mg/m2 ). The effects of different doses of PLD on clinical efficacy, cardiotoxicity and prognosis of patients were retrospectively analyzed. Subgroup analysis was performed to compare the clinical characteristics of different subgroups. RESULTS: Our study showed that PLD and epirubicin had similar efficacy (overall survival (OS) p = 0.776; progression-free survival (PFS) p = 0.959). RCDOP (30-45 mg/m2 PLD) group had a higher complete remission (CR) rate of 75.9% compared with RCdOP (20-30 mg/m2 PLD) group (P D vs. d = 0.018). In the overall population, there was no significant difference in survival between RCDOP and RCdOP groups (OS P D vs. d = 0.661; PFS P D vs. d = 0.212). In patients with underlying cardiovascular diseases, the PFS of the RCDOP group was significantly better than the RCdOP group (p = 0.043). Meanwhile, patients in the RCDOP group tended to have a better prognosis than those in the RCEOP group (OS: RCDOP vs. RCEOP p = 0.054, PFS: RCDOP vs. RCEOP p = 0.053). There was no significant difference in the incidence of cardiotoxicity and other adverse events among the three groups. For the low-risk (age-adjusted-International Prognostic Index = 0/1) old patients without cardiovascular disease, RCdOP was considered a better strategy in OS (p = 0.020). CONCLUSION: In the general population, the CR rate in the RCDOP group was significantly higher than that in the RCdOP group (p = 0.018). For elderly DLBCL patients with cardiovascular disease, the effect benefit brought by the PLD dose was more obvious, and the PFS of the RCDOP group was significantly better than that of the RCdOP group (p = 0.043). Full dose of PLD is an efficient alternative in the treatment of patients with preexisting cardiovascular diseases.

Loncastuximab tesirine: an effective therapy for relapsed or refractory diffuse large B-cell lymphoma.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is the most common type of Non-Hodgkin's lymphoma in the United States, with approximately 40% of first-line DLBCL chemoimmunotherapy attempts failing. The FDA approved a new type of antibody-drug conjugate (ADC), Zynlonta (loncastuximab tesirine), once called ADCT-402, on April 23, 2021, for relapsed or refractory (R/R) DLBCL. Loncastuximab tesirine comprises a humanized anti-CD19 monoclonal antibody conjugated to a pyrrolobenzodiazepine dimer toxin.  PURPOSE: The purpose of this article is to review the pharmacological properties of loncastuximab tesirine and evaluate its efficacy and safety in the treatment of R/R DLBCL. METHODS: In PubMed, Web of Science and CNKI, I searched for relevant literature as of November 2021 through some keywords. Obtained loncastuximab tesirine essential drug and related clinical trial information on https://www.adctherapeutics.com/ and clinicaltrials.gov. RESULTS: Once it binds with cells expressing CD19, loncastuximab tesirine is internalized by the cell and then releases SG3199, which irreversibly binds to the DNA, thereby disrupting the basic DNA metabolism process and ultimately leading to cell death. The results of the main non-comparative clinical trials LOTIS-1, LOTIS-2 and LOTIS-3 were encouraging. In LOTIS-1, the overall response rate (ORR) of R/R DLBCL patients treated with loncastuximab tesirine was 42.3%, and loncastuximab tesirine had excellent stability and acceptable safety profile. The recommended dosage of loncastuximab tesirine is 0.15 mg/kg every three weeks for two cycles, 0.075 mg/kg every three weeks for each subsequent cycle. The pivotal LOTIS-2 showed that loncastuximab tesirine had substantial single-agent antitumour activity in patients with R/R DLBCL: the ORR and complete response rate were 48.3% and 24.1%, respectively, and produced a durable response with acceptable safety and tolerability. The results of the LOTIS-3 phase 1 portion indicated that loncastuximab tesirine 60 µg/kg plus ibrutinib 560 mg had encouraging antitumour activity in R/R DLBCL, with an ORR of 56.7%. Haematological adverse events such as anaemia and neutropenia, non-haematological events such as fatigue and nausea, and biochemical events such as γ-glutamyl transferase increase, and blood alkaline phosphatase increases were common after administration of loncastuximab tesirine. CONCLUSIONS: Loncastuximab tesirine is a CD19-targeted ADC that addresses the unmet needs of R/R DLBCL patients who have been heavily pretreated, comprising high-risk populations.

Polatuzumab-based regimen or CAR T cell for patients with refractory/relapsed DLBCL-a matched cohort analysis.

Polatuzumab (Pola)-based regimens and chimeric antigen receptor T (CAR T) cells provide superior outcome compared to conventional chemoimmunotherapy in patients with relapsed/refractory diffuse large B cell lymphoma (R/R DLBCL). Choosing between these strategies remains controversial. The efficacy of CAR T versus Pola-rituximab(R) /Pola-bendamustine(B)-R in R/R DLBCL patients after failing ≥2 lines of treatment was compared in a retrospective, 'real-world' study. Propensity score matching, for age, lymphoma category (de-novo/transformed), number of prior lines, Eastern Cooperative Oncology Group performance status and lactate dehydrogenase level, was applied to control for differences in patients' characteristics. Response rate, progression-free survival (PFS) and overall survival (OS) were analyzed. A total of 82 patients, treated with CAR T (n=41) or Pola-based regimens (n=41), were included. No treatment-related deaths occurred with CAR T vs. 3 (7.3%) with Pola. The overall and complete response rates were 83% and 58% with CAR T vs. 66% and 44% with Pola-based-regimens (p=0.077 and p=0.18, respectively). At a median follow-up of 9 months (range 1-19.2) and 16 months (range 0.7-25.3) for the CAR T and Pola arm respectively, the median PFS has not been reached for CAR T vs. 5.6 months for Pola (95% CI 3.6-7.6, p=0.014). Median OS has not been reached for CAR T vs. 10.8 months (95% CI 2.2-19.4) for Pola (p=0.026). To conclude, in a real-world setting, treatment with CAR T achieved superior PFS and OS compared to Pola-based regimens in patients with R/R DLBCL.

PD-L1 expression is associated with the spontaneous regression of patients with methotrexate-associated lymphoproliferative disorders.

BACKGROUND: Most patients with methotrexate-associated lymphoproliferative disorder (MTX-LPD) show diffuse large B-cell lymphoma (DLBCL) or classic Hodgkin lymphoma (CHL) types. Patients with MTX-LPD often have spontaneous remission after MTX discontinuation, but chemotherapeutic intervention is frequently required in patients with CHL-type MTX-LPD. In this study, we examined whether programmed cell death-ligand 1 (PD-L1) expression levels were associated with the prognosis of MTX-LPD after MTX discontinuation. METHODS: A total of 72 Japanese patients diagnosed with MTX-LPD were clinicopathologically analyzed, and immunohistochemical staining of PD-L1 was performed in 20 DLBCL-type and 24 CHL-type MTX-LPD cases to compare with the clinical course. RESULTS: PD-L1 was expressed in 5.0% (1/20) of patients with DLBCL-type MTX-LPD, whereas it was expressed in 66.7% (16/24) of the patients with CHL-type MTX-LPD in more than 51% of tumor cells. Most CHL-type MTX-LPD patients with high PD-L1 expression required chemotherapy owing to exacerbations or relapses after MTX discontinuation. However, no significant differences in clinicopathologic findings at diagnosis were observed between PD-L1 high- and low-expression CHL-type MTX-LPD. CONCLUSION: PD-L1 expression was significantly higher in patients with CHL-type than DLBCL-type MTX-LPD, suggesting the need for chemotherapy in addition to MTX discontinuation in CHL-type MTX-LPD patients to achieve complete remission. No association was observed between PD-L1 expression levels and clinical findings at diagnosis, suggesting that PD-L1 expression in tumor cells influences the pathogenesis of CHL-type MTX-LPD after MTX discontinuation.

Efficacy and Safety Exposure-Response Analysis of Loncastuximab Tesirine in Patients with B cell non-Hodgkin Lymphoma.

We developed an integrated population pharmacokinetic model to investigate loncastuximab tesirine pharmacokinetics (PK) and exposure-response relationships for relapsed/refractory B cell non-Hodgkin lymphoma, including diffuse large B cell lymphoma (DLBCL). The model, based on the recommended dosing schedule (150 µg/kg every 3 weeks [Q3W] for 2 cycles; 75 µg/kg Q3W thereafter) and drug concentrations in phase 1 and 2 studies (DLBCL [n = 284], non-DLBCL [n = 44]), was used to characterize loncastuximab tesirine PK and evaluate exposure covariates. Relationships between exposure (pyrrolobenzodiazepine-conjugated antibody [cAb] cycle 1 average concentration) and (1) efficacy (including overall response rate [ORR; primary endpoint] and overall survival [OS]) and (2) grade ≥ 2 treatment-emergent adverse events were explored. Statistical analyses included univariate and multivariate logistic regression, Kaplan-Meier analysis, and Cox proportional hazard regression. cAb and total Ab were best described by a two-compartment linear model with time-dependent clearance. The cAb steady-state half-life increased to 20.6 days by ~ 15 weeks. cAb exposure was lower for low albumin, mild/moderate hepatic impairment, non-DLBCL subtypes, and Eastern Cooperative Oncology Group scores > 1. Significant positive associations were reported between exposure and ORR (p = 3.21E-6), OS (p = 0.0016), grade ≥ 2 increased gamma-glutamyltransferase, liver function test abnormalities, pain, and skin/nail reactions (p < 0.05). Low albumin, bulky disease, and mild/moderate hepatic impairment had a significant negative effect on OS (p < 0.01). Modeling supports the recommended loncastuximab tesirine dosing schedule. Although reduced exposure and efficacy were predicted for specific covariates (e.g., low albumin, mild/moderate hepatic impairment), dose increases are not recommended. Trial registration: NCT02669017 and NCT03589469.

Evaluating efficacy and safety of loncastuximab tesirine injection for the treatment of adult patients with relapsed or refractory large B-cell lymphoma.

INTRODUCTION: Relapsed or refractory diffuse large B cell lymphoma (DLBCL) has a poor prognosis. Several novel therapies have gained regulatory approval for treatment of DLBCL, however there is still a need for additional therapies to be added to the armamentarium. Loncastuximab tesirine-lpyl (ADC Therapeutics), an anti-CD19 antibody-drug conjugate (ADC), was recently approved for the treatment of relapsed, refractory diffuse large B-cell lymphoma (DLBCL). AREAS COVERED: We review the design and pharmacologic characteristics of loncastuximab tesirine-lpyl, emphasizing on the significance of CD19 as an effective target as well as pyrrolobenzodiazepine (PBD) as an effective payload. We review the key findings of the phase 1 LOTIS-1 and Phase 2 LOTIS-2 trials of loncastuximab in DLBCL, including efficacy and toxicity profile. EXPERT OPINION: Key findings in the early-phase trial support the efficacy of Loncastuximab in DLBCL, including in high-risk subgroups. The side effects have been tolerable even in elderly patients (≥75 years). Several ongoing clinical trials are currently evaluating the safety and efficacy of loncastuximab tesirine in a variety of NHL subtypes, as well as the study of combination strategies.

Retrospective analyses of other iatrogenic immunodeficiency-associated lymphoproliferative disorders in patients with rheumatic diseases.

Other iatrogenic immunodeficiency-associated lymphoproliferative disorders (OIIA-LPDs) occur in patients receiving immunosuppressive drugs for autoimmune diseases; however, their clinicopathological and genetic features remain unknown. In the present study, we analysed 67 patients with OIIA-LPDs, including 36 with diffuse large B-cell lymphoma (DLBCL)-type and 19 with Hodgkin lymphoma (HL)-type. After discontinuation of immunosuppressive drugs, regression without relapse was achieved in 22 of 58 patients. Spontaneous regression was associated with Epstein-Barr virus positivity in DLBCL-type (P = 0·013). The 2-year overall survival and progression-free survival (PFS) at a median follow-up of 32·4 months were 92·7% and 72·1% respectively. Furthermore, a significant difference in the 2-year PFS was seen between patients with DLBCL-type and HL-type OIIA-LPDs (81·0% vs. 40·9% respectively, P = 0·021). In targeted sequencing of 47 genes in tumour-derived DNA from 20 DLBCL-type OIIA-LPD samples, histone-lysine N-methyltransferase 2D (KMT2D; eight, 40%) and tumour necrosis factor receptor superfamily member 14 (TNFRSF14; six, 30%) were the most frequently mutated genes. TNF alpha-induced protein 3 (TNFAIP3) mutations were present in four patients (20%) with DLBCL-type OIIA-LPD. Cases with DLBCL-type OIIA-LPD harbouring TNFAIP3 mutations had shorter PFS and required early initiation of first chemotherapy. There were no significant factors for spontaneous regression or response rates according to the presence of mutations. Overall, OIIA-LPDs, especially DLBCL-types, showed favourable prognoses.

[Oral Mucosal Diffuse Large B-cell Lymphoma Caused by Long-term Oral Methotrexate:Report of One Case].

A case of primary oral mucosal diffuse large B-cell lymphoma(DLBCL)due to long-term use of methotrexate(MTX)for the treatment of rheumatoid arthritis(RA)was admitted to the Department of Hematology,Fujian Medical University Union Hospital.We analyzed and discussed the clinical features,diagnosis and treatment,and prognosis of specific malignant lymphoma induced by MTX in this RA patient.Our purpose is to improve the awareness and knowledge of other iatrogenic immunodeficiency-associated lymphoproliferative disorders of clinicians and pathologists.This study provides a new reference for the clinical diagnosis and treatment of MTX-associated DLBCL.

Primary cutaneous diffuse large B-cell lymphoma, leg type, in a patient with rheumatoid arthritis undergoing etanercept therapy.

An 84-year-old woman, who was diagnosed with rheumatoid arthritis (RA) and was treated with methotrexate and, subsequently, etanercept (ETN) for 6 years, presented with rapidly progressing painful cutaneous mass on the right medial malleolus. The patient was eventually diagnosed with primary cutaneous diffuse large B-cell lymphoma, leg type (PCLBCL-LT). ETN therapy was promptly discontinued expecting spontaneous regression of the lymphoma, which was thought to have developed as other iatrogenic immunodeficiency-associated lymphoproliferative disorders. However, no tumour regression was noted. Chemoimmunotherapy was subsequently initiated, which resulted in partial remission. PCLBCL-LT rarely occurs in patients with RA. Here, we report the first case of PCLBCL-LT that developed in a patient with RA receiving ETN therapy.

Clinicopathological evaluation of methotrexate-associated lymphoproliferative disorders with special focus on Epstein-Barr virus-positive mucocutaneous lesions.

Some patients diagnosed with methotrexate-associated lymphoproliferative disorder (MTX-LPD) develop spontaneous regression upon the discontinuation of MTX, whereas others require chemotherapy. The mechanisms underlying this differential response and the capacity to spontaneously regress are not clearly understood. We evaluated numerous clinicopathological features in 63 patients diagnosed with MTX-LPD, with a special focus on those with Epstein-Barr virus (EBV)-positive mucocutaneous lesions (EBVMCL). The diagnosis of EBVMCL included cases of both EBV-positive mucocutaneous ulcers (EBVMCU) and diffuse gingival swelling associated with proliferation of EBV-positive large B-cells. Of the four subgroups of MTX-LPD, one-year treatment-free survival (TFS) after the discontinuation of MTX was achieved among those with EBVMCL (100%), diffuse large B-cell lymphoma (57%), Hodgkin-like lesions (60%), or classical Hodgkin lymphoma (29%); a significant difference in TFS was observed when comparing the responses of patients with EBVMCL to the those diagnosed with other subtypes. Multivariate analysis revealed predictive factors for prolonged TFS that included EBV-positive lesions and comparatively low levels of serum LDH. Taken together, our study suggests that a diagnosis of EBVMCL is related to the overall clinical outcome after the discontinuation of MTX.

Linfoma difuso de células grandes B asociado a metotrexato en un paciente afecto de una leucemia linfoblástica aguda / Diffuse large B cell lymphoma associated with methotrexate in a patient with acute lymphoblastic leukemia

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Association Between Pesticide Use and Incidence of Diffuse Large B-Cell Lymphoma.

BACKGROUND/AIM: Exposure to pesticides has been reportedly associated with several types of cancer. MATERIALS AND METHODS: In this study, we used data from The United States Geological Survey (USGS), United States Census, and the Surveillance, Epidemiology, and End Results (SEER) database to analyze the association between the area density of specific agricultural pesticides and the county level annual incidence of diffuse large B-cell lymphoma (DLBCL). RESULTS: Incidence of DLBCL was significantly associated with an area density of 14 of the pesticides reported by USGS. CONCLUSION: This highlights the need for further investigation into the safety of the use of these pesticides. The importance of this study comes not only from the significant association it shows between pesticides and the incidence of cancer, but also from the fact that it included all compounds reported to USGS as being used in agriculture. This helps in prioritizing pesticides for further evaluation.

Methotrexate-induced Primary Cutaneous Diffuse Large B-cell Lymphoma in Patients with Erythrodermic Cutaneous T-cell Lymphoma.

is missing (Short communication).

Insecticide use and risk of non-Hodgkin lymphoma subtypes: A subset meta-analysis of the North American Pooled Project.

Insecticide use has been linked to increased risk of non-Hodgkin lymphoma (NHL), however, findings of epidemiologic studies have been inconsistent, particularly for NHL subtypes. We analyzed 1690 NHL cases and 5131 controls in the North American Pooled Project (NAPP) to investigate self-reported insecticide use and risk of NHL overall and by subtypes: follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL) and small lymphocytic lymphoma (SLL). Odds ratios (OR) and 95% confidence intervals for each insecticide were estimated using logistic regression. Subtype-specific associations were evaluated using ASSET (Association analysis for SubSETs). Increased risks of multiple NHL subtypes were observed for lindane (OR = 1.60, 1.20-2.10: FL, DLCBL, SLL), chlordane (OR = 1.59, 1.17-2.16: FL, SLL) and DDT (OR = 1.36, 1.06-1.73: DLBCL, SLL). Positive trends were observed, within the subsets with identified associations, for increasing categories of exposure duration for lindane (Ptrend = 1.7 × 10-4 ), chlordane (Ptrend = 1.0 × 10-3 ) and DDT (Ptrend = 4.2 × 10-3 ), however, the exposure-response relationship was nonlinear. Ever use of pyrethrum was associated with an increased risk of FL (OR = 3.65, 1.45-9.15), and the relationship with duration of use appeared monotonic (OR for >10 years: OR = 5.38, 1.75-16.53; Ptrend = 3.6 × 10-3 ). Our analysis identified several novel associations between insecticide use and specific NHL subtypes, suggesting possible etiologic heterogeneity in the context of pesticide exposure.

A case of bilateral methotrexate-associated diffuse large B-cell lymphomas of the breasts with unique clinical presentation and outcome.

A 54-year-old woman on methotrexate (MTX) treatment developed reddish skin change in her right breast. Mammography and ultrasound showed no masses in the breasts but bilateral mammary glands presented diffuse lower-level echoes. Only 19 days later, the patient developed bilateral breast masses. Histological examination showed that diffuse large B-cell lymphoma cells spread widely and sparsely in the bilateral breasts in addition to the tumor cell conglomerate, leading to the diagnosis of MTX-associated lympho-proliferative disorders (MTX-LPDs). Withdrawal of MTX resulted in complete disappearance of the left MTX-LPD in 2 months but no regression of the right MTX-LPD. Chemotherapy led to a partial response followed by re-growth of the right MTX-LPD. Re-biopsy of the right MTX-LPD revealed double/triple hit lymphoma. Second-line and later-line chemotherapies caused no regression of the right MTX-LPD. The patient died in a year after the diagnosis of MTX-LPDs. Breast oncologists should note the presence, biology, and diagnostic images of MTX-LPD.