A Fondazione Italiana Linfomi cohort study of R-COMP vs R-CHOP in older patients with diffuse large B-cell lymphoma.

Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is the most commonly used regimen for the upfront treatment of diffuse large B-cell lymphoma (DLBCL). However, it is associated with cardiotoxicity, especially in older patients. Substituting doxorubicin with non-PEGylated liposomal doxorubicin (R-COMP) may reduce the risk of cardiac events, but its efficacy has never been demonstrated in prospective trials. We describe the characteristics and outcome of patients with DLBCL aged ≥65 years prospectively enrolled in the Elderly Project by the Fondazione Italiana Linfomi and treated with full doses of R-CHOP or R-COMP per local practice. Starting from 1163 patients, 383 (55%) were treated with R-CHOP and 308 (45%) with R-COMP. Patients treated with R-COMP were older (median age, 76 vs 71 years), less frequently fit at simplified geriatric assessment (61% vs 88%; P < .001), and had a more frequent baseline cardiac disorders (grade >1, 32% vs 8%; P < .001). Three-year progression-free survival (PFS) was similar between R-CHOP and R-COMP (70% and 64%); 3-year overall survival was 77%, and 71% respectively. R-CHOP was associated with better PFS vs R-COMP only in the Elderly Prognostic Index (EPI) low-risk group. The two groups had similar rates of treatment interruptions due to toxicities or of cardiac events (P = 1.00). We suggest R-COMP is a potentially curative treatment for older patients with intermediate- or high-risk EPI, even in the presence of a baseline cardiopathy. R-CHOP is confirmed as the standard therapy for low risk patients.

Non-Hodgkin Lymphoma Developed Shortly after mRNA COVID-19 Vaccination: Report of a Case and Review of the Literature.

We report on a 66-year-old man who presented with a right axillary lymphadenopathy approximately 10 days after receiving the third dose of the BNT162b2 vaccine. The lymphadenopathy gradually enlarged, and physical examination and ultrasound (US) revealed one right axillary 6.99 cm and one right supraclavicular 2.36 cm lymphadenopathy. Histologic examination of the right axillary nodule revealed anaplastic large-cell lymphoma that was ALK negative and CD30 positive. A total body computerized tomography (CT) scan, positron emission tomography (PET) and bone-marrow biopsy showed a stage-II non-Hodgkin lymphoma (NHL). The patient was treated with chemotherapy and a scheme of Brentuximab Vedotin, Cyclophosphamide, Doxorubicin and Prednisone (BV-CHP) for six cycles and is now well and in complete remission. The revision of the literature revealed eight additional cases of NHL developed shortly after COVID-vaccination. There were four cases of diffuse large-B-cell lymphoma (DLBCL) (one in a patient who was a heart transplant recipient and developed an Epstein-Bar-virus-positive DLBCL), one case of extranodal NK/T-cell lymphoma, one patient with subcutaneous panniculitis-like T-cell lymphoma, one case of marginal zone B-cell lymphoma and one primary cutaneous anaplastic large-cell lymphoma (PC-ALCL). In five cases, the lymphoma developed after BNT162b2 mRNA vaccination, including one case after ChAdOx1 nCOV-19, one case after the adenovirus type 26 (Ad26) vaccine and one after mRNA-1273/Spikevax (ModernaTX). We are aware that the link between COVID-19 vaccination and lymphoma most likely is a chance phenomenon, and that COVID-19 vaccines represent very efficient products for many people around the world. However, we believe that clinical events, even if only temporally associated with novel treatments or novel vaccines, should be reported for the benefit of the patients and the scientific community.

Case report: Senescence as mechanism of resistance to Pembrolizumab in a Lymphoma patient who failed CD19-Targeted CAR-T cell therapy.

Background: T cells engineered to target CD19 antigen on neoplastic B cells represent the most striking example of CAR-T cell therapy. The success rate of this therapy is affected by several limitations: target antigen loss, and/or acquisition of a senescent/exhausted phenotype by CAR and non-CAR T cells. Case presentation: We report on a patient affected by refractory Diffuse Large B-cell Lymphoma who was resistant to CAR T-cell therapy and to two cycles post CAR-T of pembrolizumab (PBZ) due to the evolution into a B-cell Hodgkin-like lymphoma. Owing to the CD30 expression and the Hodgkin-like phenotype, the patient was ultimately treated with Brentuximab-Vedotin and finally underwent remission. Upon PBZ treatment, 100% of circulating CAR-T+ cells showed a persistent CD8+ senescent/exhausted phenotype, while an increase in the percentage of senescent cells was found in the non-CAR CD8+ T cells compartment. Conclusions: PBZ is not able to reinvigorate exhausted CAR+ T cells and to confer durable clinical response. We hypothesize that the phenomenon is due to the senescent phenotype of CAR+ T cells, which did not allow PBZ-induced reactivation and proliferative rescue. The phenomenon, together with the loss of CAR-T target CD19 and the shift of non-CAR CD8+ T cells towards a senescent phenotype likely contributed to set up an immune landscape with poor antitumor capacity.

COVID-19 vaccines in adult cancer patients with solid tumours undergoing active treatment: Seropositivity and safety. A prospective observational study in Italy.

INTRODUCTION: Patients with cancer are presumed a frail group at high risk of contracting coronavirus disease (COVID-19), and vaccination represents a cornerstone in addressing the COVID-19 pandemic. However, data on COVID-19 vaccination in cancer patients are fragmentary and poor. METHODS: An observational study was conducted to evaluate the seropositivity rate and safety of a two-dose regimen of the BNT162b2 or messenger RNA-1273 vaccine in adult patients with solid cancer undergoing active anticancer treatment or whose treatment had been terminated within 6 months of the start of the study. The control group was composed of healthy volunteers. Serum samples were evaluated for SARS-COV-2 antibodies before vaccinations and 2-6 weeks after the administration of the second vaccine dose. Primary end-point: seropositivity rate. Secondary end-points: safety, factors influencing seroconversion, IgG titers of patients versus healthy volunteers, COVID-19 infection. RESULTS: Between 20th March 2021 and 12th June 2021, 293 consecutive patients with cancer-solid tumours underwent a program of COVID-19 vaccinations; of these, 2 patients refused vaccination, 13 patients did not receive the second dose of the vaccine because of cancer progression, and 21 patients had COVID-19 antibodies at baseline and were excluded. The 257 evaluable patients had a median age of 65 years (range 28-86), 66.15% with metastatic disease. Primary end-point: seropositivity rate in patients was 75.88% versus 100% in the control group. Secondary end-points: no Grade 3-4 side-effects, no COVID-19 infections were reported. Patients median IgG titer was significantly lower than in the control group; male sex and active anticancer therapy influenced negative seroconversion. BNT162b2 or messenger RNA-1273 vaccines were immunogenic in cancer patients, showing good safety profile.

Case Report: B Lymphocyte Disorders Under COVID-19 Inflammatory Pressure.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infects humans through the angiotensin converting enzyme-2 (ACE-2) receptor expressed on many cells, including lymphocytes. In Covid-19 patients IL-6 is overexpressed, and hyperactivated plasmacytoid lymphocytes are detected in peripheral blood film. We hypothesize that, due to the unpredictable interaction between the new virus and the B cell lineage of infected patients, a cascade of out of control events can ensue, capable of determining unexpected pathologic disorders involving such lineage. Here we report two cases of autoimmune hemolytic anemia (AIHA) and two cases of B-cell hematological malignancies developed or reactivated during acute SARS-CoV-2 infection. The temporal relationship of the events may suggest a potential causal relationship between SARS-CoV-2 infection and the hematopoietic disorders. We suggest that special attention should be paid to COVID-19 patients with underlining B cell lineage disorders.

Safety and efficacy of rituximab plus bendamustine in relapsed or refractory diffuse large B-cell lymphoma patients: an Italian retrospective multicenter study.

Relapsed or refractory diffuse large B-cell lymphoma (DLBCL) not suitable for high dose chemotherapy with autologous stem cell transplantation (ASCT) has a dismal prognosis and no standard therapy. We designed an Italian multicenter retrospective study aimed at evaluating the safety and efficacy of rituximab plus bendamustine (R-B) as salvage treatment in patients not eligible for ASCT because of age and/or comorbidity or in patients with post-ASCT recurrence. Fifty-five patients with a median age of 76 years were included. The overall response rate was 50%, including 28% complete remission and 22% partial remission. The median overall survival (OS) was 10.8 months. The median progression free survival (PFS) was 8.8 months. Eleven patients are still alive and in complete remission at last follow-up (12-71 months). Toxicity was moderate, mainly grades 1 and 2. R-B showed promising efficacy results with an acceptable toxicity profile and should be further investigated, possibly in combination with novel drugs.

Safety and efficacy of granulocyte colony-stimulating factor biosimilars in engraftment after autologous stem cell transplantation for haematological malignancies: a 4-year, single institute experience with different conditioning regimens.

BACKGROUND: Filgrastim biosimilars have recently been introduced into clinical practice. To date biosimilars have demonstrated comparable efficacy and safety as the originator in chemotherapy-induced neutropenia. Published experience in engraftment after autologous stem cell transplantation (ASCT) is limited and concerns relatively few patients. MATERIALS AND METHODS: With the aim of assessing the efficacy and the safety of filgrastim biosimilars in post-ASCT bone marrow recovery, we conducted a single institution, retrospective study in 56 lymphoma and myeloma patients who received filgrastim biosimilars (Tevagrastim(®) and Zarzio(®)) at standard doses from day 5. We compared our results with recently published data on the originator. A cost analysis of each biosimilar was performed. RESULTS: Neutrophil counts recovered in 55 patients. The median number of filgrastim biosimilar vials injected was seven per patient. The median time to neutrophil and platelet recovery was 10 and 12 days, respectively. Twenty-six patients had febrile neutropenia, in half of whom the agent involved was identified. In the cost analysis, the use of Tevagrastim(®) and Zarzio(®) was associated with cost reductions of 56% and of 86%, respectively. DISCUSSION: Despite differences in CD34+ cell counts and time of starting filgrastim, our results in terms of time to engraftment and median number of vials injected are similar to published data. Comparing our results by single conditioning regimen to recent literature data, the time to engraftment and duration of hospitalisation were equivalent. Significant differences were observed in the incidence of febrile neutropenia, perhaps due to different preventive and prophylactic protocols for infections. Although prospective studies should be performed to confirm our results, filgrastim biosimilars were found to be effective and safe in engraftment after ASCT.

Inversion time prolongation at late enhancement cardiac MRI in a myeloma patient.

A patient undergoing chemotherapy for multiple myeloma had a sudden onset of heart failure. Cardiac magnetic resonance was performed after echocardiography to rule out myocardial late enhancement, which was not detected. In- terestingly, the inversion time of the T1-weighted inversion recovery late enhancement sequence needed to be significantly increased (from the usual 250-300 to 490 ms) to obtain diagnostic images. This report presents the clinical case of this patient, and discusses potential implications.

[Thrombotic thrombocytopenic purpura: report of seven cases]. / Porpora trombotica trombocitopenica: descrizione di sette casi.

From May 1999 to January 2002 we observed 7 patients (4 females and 3 males, median age 55 years, range 31-81 years) with thrombotic thrombocytopenic purpura (TTP). Six patients has been previously undiagnosed and 1 patient was at second relapse. Trigger factors of TTP were identified in 6 patients: ticlopidine treatment (2 patients); an acute cutaneous infection episode immediately before the features of TTP (1 patient); presence of devices: orthodontic (1 patient) and intrauterine contraceptive (1 patient), Mycoplasma urealyticum vaginal infection (1 patient). In all the 7 patients the clinical status was mainly related to the hemolytic anemia, thrombocytopenia and neurological events. One of these patients presented with hemolytic-uremic syndrome with acute renal failure and macrohematuria at onset, another one showed a systemic exanthema post-infection-like. Six out of 7 patients presented with different neurological events: headache, confusion, focal neurological failure. All the 7 patients were promptly treated with plasma-exchange and cryosupernatant plasma infusion. In addition they received prednisone 25-50 mg/day. All the 7 patients achieved a complete remission after plasma-exchange, one relapsed 3 months later and was treated with plasma-exchange again. All the patients are in complete remission with a median follow-up of 36.3 months (range 20-62 months). From these cases we suggest: 1) clinicians should take in mind the suspicion of TTP in every patient with hemolytic, negative direct Coombs test, anemia, thrombocytopenia, high level of lactate dehydrogenase; 2) the treatment of choice is plasma-exchange; 3) the response of treatment is good if therapy is promptly and aggressively administered; 4) the possible role of a trigger factor for removing it and to prevent relapses.

Primary pancreatic lymphoma. Report of five cases.

Primary pancreatic lymphoma (PPL) is a very rare disease. We report five cases of PPL (4 men and 1 woman, mean age 65 years) diagnosed and treated at our Institution from 1987 to 1997. None of these patients had evidence of extrapancreatic disease and they were categorized as PPL involving pancreas only (stage IE, 3 patients) or pancreas and peripancreatic lymph nodes (stage IIE, 2 patients). The most common presenting symptoms were abdominal pain and weight loss. Imaging techniques showed a mass of the pancreatic head in all cases. The histological diagnosis (3 diffuse-large cell non-Hodgkin's lymphoma and 2 lymphoplasmacytic lymphoma/immunocytoma) was made by ultrasound-guided fine needle aspiration biopsy and tissue core fine-needle biopsy in three patients and by surgery in the remaining two patients. The three patients diagnosed by percutaneous biopsy were treated with chemotherapy as front-line therapy and two of them received also local radiotherapy; one of these patients is still alive in complete remission at 69 months, one died of an unrelated disease at 67 months and one died of lymphoma relapse at 88 months. Two patients underwent pancreaticoduodenectomy plus adjuvant chemotherapy; one of them died of recurrent cholangitis 8 months after surgery while the other one is still alive in complete remission after 160 months. This study shows that: 1) imaging techniques can suggest the suspicion of PPL but are unable to distinguish PPL from pancreatic adenocarcinoma; 2) histological diagnosis can be easily obtained by percutaneous US-guided tissue core biopsy; 3) surgery can be avoided both for diagnosis and therapy but the treatment of choice of PPL may only be evaluated on a larger series of patients.

Role of anti-hepatitis C virus (HCV) treatment in HCV-related, low-grade, B-cell, non-Hodgkin's lymphoma: a multicenter Italian experience.

PURPOSE: Hepatitis C virus (HCV) is endemic in some areas of Northwestern Europe and the United States. HCV has been shown to play a role in the development of both hepatocellular carcinoma and B-cell non-Hodgkin's lymphoma (B-NHL). The biologic mechanisms underlying the lymphomagenic activity of the virus so far are under investigation. In this study, the role of antiviral (anti-HCV) treatment in B-NHL associated with HCV infection is evaluated. PATIENTS AND METHODS: Thirteen patients with histologically proven low-grade B-NHL characterized by an indolent course (ie, doubling time no less than 1 year, no bulky disease) and carrying HCV infection were enrolled on the study. All patients underwent antiviral treatment alone with pegilated interferon and ribavirin. Response assessment took place at 6 and 12 months. RESULTS: Of the twelve assessable patients, seven (58%) achieved complete response and two (16%) partial hematologic response at 14.1 +/- 9.7 months (range, 2 to 24 months, median follow-up, 14 months), while two had stable disease with only one patient experiencing progression of disease. Hematologic responses (complete and partial, 75%) were highly significantly associated to clearance or decrease in serum HCV viral load following treatment (P = .005). Virologic response was more likely to be seen in HCV genotype 2 (P = .035), while hematologic response did not correlate with the viral genotype. Treatment-related toxicity did not cause discontinuation of therapy in all but two patients, one of whom, however, achieved complete response. CONCLUSION: This experience strongly provides a role for antiviral treatment in patients affected by HCV-related, low-grade, B-cell NHL.

Safety and efficacy of enoxaparin treatment in venous thromboembolic disease during acute leukemia.

BACKGROUND: Venous thromboembolism (VTE) is a quite common complication in acute leukemia, although its real incidence is unknown. The best treatment of this complication is still a matter of debate due to the very high risk of hemorrhage in this group of patients. PATIENTS AND METHODS: From December 2000 to December 2002 four Caucasian patients with acute leukemia developed VTE complications. The patients were three men and one woman, mean age 55.7 years (range, 27-77). Two patients with acute lymphoid leukemia (L1 and L2 according to the FAB classification) developed deep venous thrombosis during the administration of chemotherapy; one patient with acute myeloid leukemia (AML, M2 according to the FAB classification) had pulmonary thromboembolism at diagnosis, while another AML patient (M4 according to FAB) showed deep venous thrombosis as the first symptom of leukemia. The clinical diagnosis of symptomatic VTE was confirmed by objective imaging procedures including lower limb venous color Doppler imaging in all cases and a ventilation-perfusion lung scan in one case. All patients were treated with enoxaparin 100 IU/kg subcutaneously twice daily for one month, followed by 150 IU/kg once daily for at least five months. When the platelet count was below 20,000 x 10(9)/L, the dose was reduced by 50%. RESULTS: During antithrombotic treatment neither VTE recurrences nor hemorrhagic complications or heparin-induced thrombocytopenia occurred. The platelet count at the beginning of enoxaparin treatment was very low (mean, 55,750 x 109/L; range, 12,000-121,000 x 10(9)/L) and treatment did not affect platelet recovery. CONCLUSIONS: Enoxaparin proved to be efficacious and safe in the management of deep venous thrombosis with or without pulmonary embolism in patients affected by acute leukemia. Enoxaparin cured acute venous thrombosis, prevented recurrences and did not cause any hemorrhagic complications despite prolonged severe thrombocytopenia.

Splenic and nodal marginal zone lymphomas are indolent disorders at high hepatitis C virus seroprevalence with distinct presenting features but similar morphologic and phenotypic profiles.

BACKGROUND: Splenic and nodal marginal zone lymphomas (MZL) are subtypes of marginal zone-derived neoplasms. Due to their rarity, little is known concerning their relation, pattern of dissemination, and treatment outcome. METHODS: The authors analyzed the clinicopathologic features and outcome of 43 patients (34 patients with splenic MZL and 9 patients with nodal MZL). All lesional tissues obtained at diagnosis were reviewed histologically. RESULTS: Among the patients with splenic MZL, 30 patients had Stage IV disease (based on the Ann Arbor staging system). Twenty-six patients presented with splenomegaly with or without limited involvement of abdominal lymph nodes, whereas 7 patients showed disease extension to superficial lymph nodes. Hepatitis C virus (HCV) serology was positive in 35% of patients. Seventeen patients underwent splenectomy, 8 patients received chemotherapy, and 7 patients were followed without initial treatment. Interferon produced a lymphoma response in three of four HCV positive patients. Of 27 treated patients, 13 patients achieved a complete response, and 12 patients achieved a partial response. The median event-free survival (EFS) was 3.3 years (5.1 years for patients with disease confined to the abdomen and 2.1 years for patients with disease extension to superficial lymph nodes). Among nine patients with nodal MZL, four patients had Stage IV disease. HCV serology was positive in two patients. Five patients responded to chemotherapy. The median EFS was 2.8 years. The median overall survival was not reached for patients with both types of MZL. CONCLUSIONS: The results of the current study demonstrated that splenic and nodal MZL are indolent lymphomas with different presenting features but common morphologic and biologic characteristics, including high HCV seroprevalence. Studies will be required to identify specific biologic markers and to define the best treatment.

Smouldering Waldenstrom's macroglobulinemia: factors predicting evolution to symptomatic disease.

Factors predicting evolution to symptomatic disease were investigated in 27 patients with smouldering Waldenstrom's macroglobulinemia (SWM) among 172 patients with Waldenstom's macroglobulinemia (WM), selected on the basis of the following criteria: (1) IgM paraprotein > 3 g/dL, and/or (2) bone marrow (BM) lymphoplasmacytoid (LPC) infiltration >or= 30%, and/or (3) diffuse infiltration pattern on BM biopsy, and (4) no treatment requirement for at least 12 months. Cumulative probability of survival was calculated by means of Kaplan-Meier. The Mantel and Haenszel test and multivariate Cox model were used to identify possible predictors for evolution. At a median follow-up of 79 months (range, 14 to 204), 11 patients (40.7%) showed progression to symptomatic disease, with the median interval from diagnosis being 46 months (range, 12 to 154). Event-free survival (EFS) at 5 and 10 years was 65% (95% confidence interval [CI], 45% to 85%) and 53% (95% CI, 31% to 75%), respectively. At multivariate analysis, paraprotein > 3 g/dL (hazard ratio [HR], 15.1; 95% CI, 3.01 to 75.64; P <.0009) and hemoglobin 3 g/dL and hemoglobin levels

Late response to cyclosporine in refractory thrombotic thrombocytopenic purpura.

Plasma exchange (PEX) with fresh frozen plasma, usually in association with steroid therapy, has been shown to be the first-line treatment of thrombotic thrombocytopenic purpura. It works by removing ultralarge von Willebrand factor (vWF) multimers and inhibitory antibody and by supplying normal protease. For patients with disease refractory to PEX, there is no standardized treatment. Limited and sporadic success with different therapies (vincristine sulfate, prostacyclin, intravenous immunoglobulins, splenectomy) has been described. We report the case of a woman who developed refractory disease after an initial response to PEX and despite a very high number of PEX procedures performed. Low activity (< 5%) of serum vWF-cleaving protease and a low level of protease inhibitor were documented. The patient had a slow but sustained response when oral cyclosporine was administered concomitantly with PEX, which was slowly tapered. The activity of serum vWF-cleaving protease normalized. At relapse, treatment with cyclosporine, added after the failure of steroids and PEX, led to a lasting response. It is possible that in some cases cyclosporine therapy must be of particularly long duration before being considered ineffective.