Transient Bacillary Layer Detachment During the Disease Course of Primary Vitreoretinal Lymphoma.

PURPOSE: To report the clinical course and the retinal imaging features of a case of cytology-proven primary vitreoretinal lymphoma (PVRL) presenting with a transient bacillary layer detachment (BALAD) during the disease course. METHODS: Observational case report. RESULTS: A 50 year-old woman was referred to us with a 2-month history of vitritis in both eyes, poorly responding to oral prednisolone. After discontinuation of oral prednisolone, worsening of vitritis and the appearance of multiple creamy-like subretinal infiltrates in the mid-peripheral retina of both eyes, along with the exclusion of common causes of intermediate/posterior uveitis, made us consider PVRL. Aqueous humor sampling detected MYD88 L265P mutation, and subsequent diagnostic pars plana vitrectomy in the left eye yielded a positive cytology for large B cell lymphoma consistent with PVRL. During the disease course, optical coherence tomography of the macula showed a BALAD in the right eye, which resolved during follow-up. CONCLUSION: Our case indicates that BALAD is a possible rare manifestation of PVRL, and this should be considered in the differential diagnosis process in order to avoid diagnostic delays.

Real-practice management and treatment of idiopathic multicentric Castleman disease with siltuximab: a collection of clinical experiences.

Castleman disease (CD) is a group of lymphoproliferative disorders that share common histopathological features yet have widely different aetiologies, clinical features and grades of severity as well as treatments and outcomes. Siltuximab is currently the only therapy approved by the FDA and EMA for idiopathic multicentric CD and is recommended as first-line therapy in treatment guidelines. Despite the extensive characterization of siltuximab treatment in clinical trials, available evidence from real-world practice is still scant. This collection of clinical experiences focuses on patients treated with siltuximab therapy, particularly regarding the idiopathic multicentric CD diagnostic work-up, and on treatment administration in patients with complex disease entering differential diagnosis with CD or concomitant diseases. Thus, these data help further characterize and improve the use of siltuximab in real practice in terms of effectiveness and safety of long-term administration as well as consequences of treatment interruption.

IELSG38: phase II trial of front-line chlorambucil plus subcutaneous rituximab induction and maintenance in mucosa-associated lymphoid tissue lymphoma.

The IELSG38 trial was conducted to investigate the effects of subcutaneous (SC) rituximab on the complete remission (CR) rate and the benefits of SC maintenance in patients with extranodal marginal zone lymphoma (MZL) who received frontline treatment with chlorambucil plus rituximab. Study treatment comprised an induction phase with chlorambucil 6 mg/m2/day orally on weeks 1-6, 9-10, 13-14, 17-18, and 21-22, and rituximab 375 mg/m2 intravenously on day 1 of weeks 1-4, and 1400 mg SC on weeks 9, 13, 17, and 21. Then, a maintenance phase followed with rituximab administered at 1400 mg SC every two months for two years. Of the 112 patients enrolled, 109 were evaluated for efficacy. The CR rates increased from 52% at the end of the induction phase to 70% upon completion of the maintenance phase. With a median follow-up of 5.8 years, the 5-year event-free, progression-free, and overall survival rates were 87% (95% CI, 78-92), 84% (95% CI, 75-89), and 93% (95% CI, 86-96), respectively. The most common grade ≥3 toxicities were neutropenia (33%) and lymphocytopenia (16%). Six patients experienced treatment-related serious adverse events, including fever of unknown origin, sepsis, pneumonia, respiratory failure, severe cerebellar ataxia, and fatal acute myeloid leukemia. The trial showed that subcutaneous rituximab did not improve the complete remission rate at the conclusion of the induction phase, which was the main endpoint. Nevertheless, SC maintenance might have facilitated long-term disease control, potentially contributing to enhanced event-free and progression-free survival.

Wait and see: a case of EBV + cutaneous extranodal NK/T-type lymphoma with indolent behaviour.

Extranodal NK/T-cell lymphoma (ENKTL) is a rare lymphoma subtype associated with Epstein-Barr virus (EBV) infection, portending a poor prognosis despite systemic chemotherapy. We present the unusual case of an 85-year-old man receiving ibrutinib for mantle cell lymphoma, who developed a erythematous, subcutaneous nodule on the forehead, featuring a proliferation of pleomorphic CD8 + /CD56 - /EBV + cells. Given the negative staging and comorbidities, a watchful waiting strategy was performed, experiencing a benign course with self-resolution and complete remission over a 4-year follow-up. The literature on primary cutaneous ENKTL has been discussed, with particular attention to clinical and histological prognostic factors.

Case report: Sodium-glucose cotransporter 2 inhibitors induce left ventricular reverse remodeling in anthracycline-related cardiac dysfunction-a case series.

Purpose: To describe the efficacy and safety of sodium-glucose cotransporter 2 inhibitors as a specific treatment for anthracycline-related cardiac dysfunction in a small real-world population. Methods: Seven patients with anthracycline-related cardiac dysfunction were clinically and echocardiographically evaluated before and after the introduction of sodium-glucose cotransporter 2 inhibitors. Results: After a median period of 24 weeks with uninterrupted sodium-glucose cotransporter 2 inhibitors treatment, a significant clinical improvement was observed with at least one New York Heart Association Functional Class (NHYA FC) improvement in all patients (median NYHA FC: I vs. III, p < 0.010). A noteworthy left ventricular reserve remodeling (median left ventricular end diastolic volume indexed: 53 vs. 82.5 ml/m2, p = 0.018; median left ventricular ejection fraction: 50% vs. 40%, p = 0.17) was also observed. Sodium-glucose cotransporter 2 inhibitors therapy was well tolerated by every patients; no cases of discontinuation or relevant side effects were observed. Conclusion: Sodium-glucose cotransporter 2 inhibitors induce a significant clinical improvement and left ventricular reserve remodeling in patients affected by anthracycline-related cardiac dysfunction.

Romidepsin-CHOEP followed by high-dose chemotherapy and stem-cell transplantation in untreated Peripheral T-Cell Lymphoma: results of the PTCL13 phase Ib/II study.

The standard treatment for young patients with untreated PTCLs is based on anthracycline containing-regimens followed by high-dose-chemotherapy and stem-cell-transplantation (HDT + SCT), but only 40% of them can be cured. Romidepsin, a histone-deacetylase inhibitor, showed promising activity in relapsed PTCLs; in first line, Romidepsin was added with CHOP. We designed a study combining romidepsin and CHOEP as induction before HDT + auto-SCT in untreated PTCLs (PTCL-NOS, AITL/THF, ALK-ALCL), aged 18-65 years. A phase Ib/II trial was conducted to define the maximum tolerated dose (MTD) of Ro-CHOEP, and to assess efficacy and safety of 6 Ro-CHOEP as induction before HDT. The study hypothesis was to achieve a 18-month PFS of 70%. Twenty-one patients were enrolled into phase Ib; 7 dose-limiting toxicities were observed, that led to define the MTD at 14 mg/ms. Eighty-six patients were included in the phase II. At a median follow-up of 28 months, the 18-month PFS was 46.2% (95%CI:35.0-56.7), and the 18-month overall survival was 73.1% (95%CI:61.6-81.7). The overall response after induction was 71%, with 62% CRs. No unexpected toxicities were reported. The primary endpoint was not met; therefore, the enrollment was stopped at a planned interim analysis. The addition of romidepsin to CHOEP did not improve the PFS of untreated PTCL patients.

Reply to "successful early use of anti-SARS-CoV-2 monoclonal neutralizing antibodies in SARS-CoV-2 infected hematological patients-A Czech multicenter experience": A case series of SARS-CoV-2 Omicron infection and aggressive lymphoma in the Sotrovimab era.

A prospective multicentre experience of early administration of anti-SARS-CoV-2 spike protein neutralizing monoclonal antibodies (MA) with efficacy among patients with hematological malignancies and early-stage COVID- 19 was reported by Weinbergerová et al. The study validated the safety and efficacy of MA early use among hematological patients with newly diagnosed early-stage COVID-19 in terms of alleviating infection course and decreasing mortality. However no reference to new variant (Delta and Omicron) or other MA (e.g., Sotrovimab) has been reported. We reported our monocentric experience of 8 aggressive lymphoma patients with Omicron infection, 7 of whom treated with this MA in our Institution between December 2021 and February 2022. Among the patients treated with Sotrovimab nobody experienced neither SARS-CoV2 reactivation, nor other infectious events. One patients on active lymphoma treatment was hospitalized for pneumonia and treated with remdesivir. In 4/8 patients negativization of molecular swab occurred concomitantly to symptoms resolution with a median of 5.25 days, while the other 4 patients remained persistently positive with a median of 26.3 days. In this group, in order to maintain the chemo/chemoimmunotherapy (CT/CIT) dose-density, lymphoma treatment was reassumed independently on molecular swab analysis. SARS-CoV-2 negativization occurred with a median of 7.7 days after the resumption of CT/CIT. The one patient treated with remdesivir, although still positive to molecular swab, restarted R-COMP regimen at symptoms resolution too, but experienced an Omicron pneumonia exacerbation. This is the first case series reported in literature of patients affected by Omicron variant in which Sotrovimab seems to provide a resolution of COVID-19 disease, even in patient with molecular swab positive persistence too. Patients with aggressive lymphoma histologies should not be deprived of the best available treatment of their disease after sotrovimab administration, even in the presence of a still positive Omicron swab.

Clinical features of type 1 and 2 refractory celiac disease: Results from a large cohort over a decade.

OBJECTIVES: Refractory celiac disease (RCeD) is a rare complication of celiac disease (CeD) with a severe prognosis. We describe a cohort of patients with RCeD, their clinical and histological features at diagnosis, after therapy and at lymphoma onset, and the rate and causes of death over a 17-year follow-up. METHODS: We retrospectively enrolled RCeD-I and RCeD-II patients attending our center between January 2002 and October 2019. Medical data were collected at diagnosis and during monitoring. Response to therapy, changes in RCeD molecular markers, number of hospitalizations, discharge diagnosis, and cause and date of death were evaluated. The control cohort consisted of 1015 responsive CeD patients. RESULTS: Compared with RCeD-I, RCeD-II more frequently exhibits diarrhea (83 vs 64%), anemia (61 vs 50%), hypoalbuminemia (70 vs 21%), parenteral nutrition need (48 vs 7%), ulcerative jejuno-ileitis (7 vs 39%), and extended small intestinal atrophy (62 vs 21%). One RCeD-I and six RCeD-II patients developed lymphoma. Ten RCeD-II patients died, four from lymphoma progression. Among RCeD-II patients, atrophy extension was the only parameter correlated with hypoalbuminemia and mortality. CONCLUSIONS: Clinical severity, response to therapy, and mortality differ between RCeD-I and RCeD-II. Atrophy extension, evaluated at capsule endoscopy, was associated with disease severity and mortality.

Real-world Outcomes of Relapsed/Refractory Diffuse Large B-cell Lymphoma Treated With Polatuzumab Vedotin-based Therapy.

After FDA and EMA approval of the regimen containing polatuzumab vedotin plus rituximab and bendamustine (PolaBR), eligible relapsed/refractory diffuse large B-cell lymphoma (DLBCL) patients in Italy were granted early access through a Named Patient Program. A multicentric observational retrospective study was conducted focusing on the effectiveness and safety of PolaBR in everyday clinical practice. Fifty-five patients were enrolled. There were 26 females (47.3%), 32 patients were primary refractory and 45 (81.8%) resulted refractory to their last therapy. The decision to add or not bendamustine was at physician's discretion. Thirty-six patients underwent PolaBR, and 19 PolaR. The 2 groups did not differ in most of baseline characteristics. The final overall response rate was 32.7% (18.2% complete response rate), with a best response rate of 49.1%. Median disease-free survival was reached at 12 months, median progression-free survival at 4.9 months and median overall survival at 9 months, respectively. Overall, 88 adverse events (AEs) were registered during treatment in 31 patients, 22 of grade ≥3. Eight cases of neuropathy occurred, all of grades 1-2 and all related to polatuzumab. The two groups of treatment did not differ for effectiveness endpoints but presented statistically significant difference in AEs occurrence, especially in hematological AEs, in AEs of grade equal or greater than 3 and in incidence of neuropathy. Our data add useful information on the effectiveness of Pola(B)R in the setting of heavily pretreated DLBCL and may also suggest a better tolerability in absence of bendamustine without compromise of efficacy.

Seroconversion to mRNA SARS-CoV-2 Vaccines in Hematologic Patients.

Hematologic patients show lower responses to SARS-CoV-2 vaccines, but predictors of seroconversion are lacking. In this prospective cohort study, hematologic patients undergoing SARS-CoV-2 mRNA vaccination at a single center in Milan, Italy, were sampled for anti-Spike and anti-Nucleocapsid IgG titer at 5 ± 1 weeks and at 3 months from the second vaccine dose. Patients (N = 393) received either BNT162b2 (Pfizer-BioNTech, 48%) or MRNA-1273 (Moderna, 52%), and 284 (72%) seroconverted and 100% persisted at 3 months. Non-response was higher in chronic lymphocytic leukemia (CLL) and lymphoma patients, and in those treated with small molecules and monoclonal antibodies. In myeloid neoplasms, lower responses were detected in patients with acute myeloid leukemia treated with venetoclax plus hypomethylating agents and in patients with myelofibrosis receiving ruxolitinib. Multivariable analysis showed that seroconversion was favorably associated with a diagnosis other than indolent lymphoma/CLL [OR 8.5 (95% CI 4.1-17.6)], lack of B-cell-depleting therapy [OR 3.15 (1.7-5.9)], and IgG levels within the normal range [OR 2.2 (1.2-4.2)]. We developed a simple algorithm according to these 3 risk factors [(A) diagnosis of indolent lymphoma/CLL, (B) B-cell-depleting treatment, and (C) low IgG] to predict non-response. IgG levels and treatment may be modifiable risk factors and should be considered for timing of vaccine administration.

Co-Occurrence of Myeloid and Lymphoid Neoplasms: Clinical Characterization and Impact on Outcome. A Single-Center Cohort Study.

The co-occurrence of myeloid neoplasms and lymphoproliferative diseases (LPDs) has been epidemiologically described, particularly in myeloproliferative neoplasms (MPNs). However, the clinical features of these patients are poorly known. In this study, we evaluated a single-center cohort of 44 patients with a diagnosis of myeloid and LPD focusing on clinical features, therapy requirement, and outcome. The two diagnoses were concomitant in 32% of patients, while myeloid disease preceded LPD in 52% of cases (after a median of 37 months, 6-318), and LPD preceded myeloid neoplasm in 16% (after a median of 41 months, 5-242). The most prevalent LPD was non-Hodgkin lymphoma (50%), particularly lymphoplasmacytic lymphoma (54.5%), followed by chronic lymphocytic leukemia (27%), plasma cell dyscrasias (18.2%), and rarer associations such as Hodgkin lymphoma and Erdheim-Chester disease. Overall, 80% of BCR-ABL1-negative MPN patients required a myeloid-specific treatment and LPD received therapy in 45.5% of cases. Seven subjects experienced vascular events, 13 a grade >/= 3 infectious episode (9 pneumonias, 3 urinary tract infection, and 1 sepsis), and 9 developed a solid tumor. Finally, nine patients died due to solid tumor (four), leukemic progression (two), infectious complications (two), and brain bleeding (one). Longer survival was observed in younger patients (p = 0.001), with better performance status (p = 0.02) and in the presence of driver mutations (p = 0.003). Contrarily, a worse survival was significantly associated with the occurrence of infections (p < 0.0001). These data suggest that in subjects with co-occurrence of myeloid and lymphoid neoplasms, high medical surveillance for infectious complications is needed, along with patient education, since they may negatively impact outcome.

Biological Difference Between Epstein-Barr Virus Positive and Negative Post-transplant Lymphoproliferative Disorders and Their Clinical Impact.

Epstein-Barr virus (EBV) infection is correlated with several lymphoproliferative disorders, including Hodgkin disease, Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL), and post-transplant lymphoproliferative disorder (PTLD). The oncogenic EBV is present in 80% of PTLD. EBV infection influences immune response and has a causative role in the oncogenic transformation of lymphocytes. The development of PTLD is the consequence of an imbalance between immunosurveillance and immunosuppression. Different approaches have been proposed to treat this disorder, including suppression of the EBV viral load, reduction of immune suppression, and malignant clone destruction. In some cases, upfront chemotherapy offers better and durable clinical responses. In this work, we elucidate the clinicopathological and molecular-genetic characteristics of PTLD to clarify the biological differences of EBV(+) and EBV(-) PTLD. Gene expression profiling, next-generation sequencing, and microRNA profiles have recently provided many data that explore PTLD pathogenic mechanisms and identify potential therapeutic targets. This article aims to explore new insights into clinical behavior and pathogenesis of EBV(-)/(+) PTLD with the hope to support future therapeutic studies.

Persistence of minimal residual disease in bone marrow predicts outcome in follicular lymphomas treated with a rituximab-intensive program.

We assessed the prognostic value of minimal residual disease (MRD) within the ML17638 phase 3 trial from the Fondazione Italiana Linfomi, investigating the role of rituximab maintenance in elderly follicular lymphoma (FL) patients after a brief first-line chemoimmunotherapy. MRD for the bcl-2/IgH translocation was determined on bone marrow cells in a centralized laboratory belonging to the Euro-MRD consortium, using qualitative and quantitative polymerase chain reactions (PCRs). Of 234 enrolled patients, 227 (97%) were screened at diagnosis. A molecular marker (MM) was found in 51%. Patients with an MM were monitored at 8 subsequent times. Of the 675 expected follow-up samples, 83% were analyzed. Conversion to PCR negativity predicted better progression-free survival (PFS) at all post-treatment times (eg, end of therapy: 3-year PFS, 72% vs 39%; P < .007). MRD was predictive in both maintenance (83% vs 60%; P < .007) and observation (71% vs 50%; P < .001) groups. PCR positivity at the end of induction was an independent adverse predictor (hazard ratio, 3.1; 95% confidence interval, 1.36-7.07). MRD is a powerful independent outcome predictor in FL patients who receive rituximab-intensive programs, suggesting a need to investigate its value for decision-making. This trial was registered at www.clinicaltrial.gov as #NCT01144364.

Darbepoetin alfa administration in patients with non-Hodgkin lymphoma and chemotherapy-induced anemia receiving (±R) CHOP.

IMPACT NHL was a multicenter, observational study in adults with non-Hodgkin lymphoma receiving CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemotherapy with or without rituximab. Erythropoietin-stimulating agent treatment was given according to routine clinical practice and physician preference. In a subanalysis, outcomes were evaluated in 207 patients who received darbepoetin alfa (DA). The most common reason (81%) for initiating DA was low/declining hemoglobin (Hb) concentration. Mean (±standard deviation) duration of DA exposure was 8.8 ± 6.9 weeks (mean number of doses, 5.1 ± 4.6). Overall, 23% of patients had chemotherapy and DA treatment synchronized more than 75% of the time. At the time of DA initiation, 67% of patients had Hb concentrations in the guideline-recommended range (9-11 g/dl). Of 89 patients with Hb concentrations <10 g/dl at DA initiation and still receiving DA 5 weeks later, 92% (Kaplan-Meier) achieved Hb concentrations 10-12 g/dl between week 5 and at the end of treatment.

Anemia and erythropoiesis-stimulating agent administration in patients with non-Hodgkin lymphoma treated with cyclophosphamide, doxorubicin, vincristine, and prednisolone ± rituximab chemotherapy: results from an observational study.

CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) ± rituximab [(± R)CHOP] is the current standard of care for aggressive non-Hodgkin lymphoma (NHL). Anemia resulting from chemotherapy can be treated with erythropoiesis-stimulating agents (ESAs). As part of the observational IMPACT NHL study, data were collected on ESA use and anemia-related outcomes in 1829 adults receiving (± R)CHOP-14 or (± R)CHOP-21. Overall, 33% of patients were anemic during chemotherapy. Older age, lower baseline hemoglobin (Hb), worse performance status, more advanced disease stage, and use of CHOP-14 were significant predictors of transfusion and anemia in logistic regression models. ESAs were received by 404 patients, usually in response to low or declining Hb levels. Most patients (65%) had Hb 9-11 g/dL at ESA initiation, and 89% (Kaplan-Meier percentage) achieved Hb 10-12 g/dL. In conclusion, two-thirds of anemic patients with NHL receiving (± R)CHOP initiated ESA treatment at Hb 9-11 g/dL, and most achieved target Hb levels (10-12 g/dL).