Sequencing novel agents in the treatment of classical Hodgkin lymphoma.

INTRODUCTION: Classical Hodgkin lymphoma (cHL) is a curable disease, with durable remission achieved in about 80% of patients following first-line treatment. Three new drugs were introduced to the daily use in cHL: brentuximab vedotin (BV), nivolumab, and pembrolizumab. All three drugs were initially approved for the treatment of relapsed/refractory cHL (RRHL) and with their promising outcomes, they are now incorporated in different stages of the treatment. AREAS COVERED: We performed a literature search using PubMed on all cHL studies investigating BV and CPIs within the past 10 years. We analyzed literature to presume the sequencing of these novel agents. EXPERT OPINION: Addition of BV or nivolumab to AVD backbone in the frontline setting showed promising activity in advanced stage cHL. BV and CPIs combined with chemotherapy in the second-line treatment of cHL are evaluated in phase 2 studies and comparable results are reported. The results of BrECADD, with good efficacy and toxicity profile, should be followed. Pembrolizumab was shown to be more effective in RRHL compared to BV in patients who have relapsed post-ASCT or ineligible for ASCT. BV is used in post-ASCT maintenance in high-risk cases, although its role will be questioned as it is increasingly used in the frontline treatment.

Glofitamab in relapsed/refractory diffuse large B-cell lymphoma: Real-world data.

Glofitamab is a CD3xCD20 bi-specific antibody with two fragments directed to the CD20 antigen and a single CD3-binding fragment. Encouraging response and survival rates were recently reported in a pivotal phase II expansion trial conducted in patients with relapsed/refractory (R/R) B-cell lymphoma. However, the real-world data of patients of all ages with no strict selection criteria are still lacking. Herein, this retrospective study aimed to evaluate the outcomes of diffuse large B-cell lymphoma (DLBCL) patients who received glofitamab via compassionate use in Turkey. Forty-three patients from 20 centers who received at least one dose of the treatment were included in this study. The median age was 54 years. The median number of previous therapies was 4, and 23 patients were refractory to first-line treatment. Twenty patients had previously undergone autologous stem cell transplantation. The median follow-up time was 5.7 months. In efficacy-evaluable patients, 21% and 16% of them achieved complete response and partial response, respectively. The median response duration was 6.3 months. The median progression-free survival (PFS) and overall survival (OS) was 3.3 and 8.8 months, respectively. None of the treatment-responsive patients progressed during the study period, and their estimated 1-year PFS and OS rate was 83%. The most frequently reported toxicity was hematological toxicity. Sixteen patients survived, while 27 died at the time of the analysis. The most common cause of death was disease progression. One patient died of cytokine release syndrome during the first cycle after receiving the first dose of glofitamab. Meanwhile, two patients died due to glofitamab-related febrile neutropenia. This is the largest real-world study on the effectiveness and toxicity of glofitamab treatment in R/R DLBCL patients. The median OS of 9 months seems promising in this heavily pretreated group. The toxicity related mortality rates were the primary concerns in this study.

Biosimilar Rituximab (Redditux) Added to CHOP Chemotherapy for De Novo Diffuse Large B-Cell Lymphoma Patients: Real-Life Single-Center Experience

Objective: Redditux® (RED), as a biosimilar rituximab, was approved in Turkey for all indications of the original Mabthera® (MAB) in March 2018. The aim of our study was to evaluate the efficacy and safety of RED in de novo diffuse large B-cell lymphoma. Materials and Methods: Fifty-one patients received RED combined with the CHOP regimen. The median follow-up was 31 months. The historical control group included 219 patients treated with the MAB-CHOP regimen and the median follow-up time was 38 months. We compared the response rates and survival outcomes of these RED-CHOP and MAB-CHOP cohorts. Results: In the RED cohort, the overall response rate (ORR) at the end of the treatment protocol was 86%, with 37 (72.5%) cases of complete response (CR) and 7 (13.5%) cases of partial response (PR). In the historical MAB cohort, the ORR was 84%, with CR and PR rates of 82% and 2%, respectively. The 24-month progression-free survival (PFS) rates were 73.76% (95% confidence interval [CI]: 0.59-0.84) and 85.2% (95% CI: 0.79-0.90) for the RED and MAB cohorts, respectively (p=0.0106). The 24-month overall survival rates were 78.4% (95% CI: 0.64-0.87) and 81.4% (95% CI: 0.75-0.86) for the RED and MAB cohorts, respectively (p=0.7461). For patients with high revised International Prognostic Index scores, 24-month PFS was 45.5% (95% CI: 0.17-0.71) and 63% (95% CI: 0.37-0.80) for the RED and MAB cohorts, respectively (p=0.0711). In the RED cohort, central nervous system (CNS) relapse was significantly increased compared to the MAB cohort (10% vs. 1.83%, p=0.004). Among the RED cohort, bone involvement at the time of diagnosis was a risk factor for CNS relapse (p=0.028). Thirteen patients died in follow-up. There were no serious adverse events causing the cessation of the drugs. Conclusion: RED has an ORR similar to that of MAB. However, PFS rates were worse in the RED cohort. Additionally, CNS relapse ratio was a major concern for our RED cohort. Large prospective controlled studies and real-life data with longer follow-up are needed to document the non-inferiority of RED compared to MAB.

Brentuximab vedotin consolidation therapy after autologous stem-cell transplantation in patients with high-risk Hodgkin lymphoma: Multicenter retrospective study.

The AETHERA trial reported an increased progression-free survival (PFS) when brentuximab vedotin (BV) was used as maintenance therapy in high-risk Hodgkin lymphoma (HL) after autologous stem cell transplantation (ASCT). Thus, we aimed to determine the impact and safety of BV as maintenance after ASCT in real-world patients. Seventy-five patients with relapsed/refractory HL started on BV consolidation therapy after ASCT due to high risk of relapse, between January 2016 and July 2019, from 25 institutions, were included in the study. The median follow-up time was 26 months. The most common high-risk features were primary refractory or relapsed disease <12 months (n = 61), lack of complete response (CR) to the last salvage regimen (n = 51), and having had at least two salvage regimens (n = 29). At the time of analysis, 42 patients completed consolidation courses, and BV was discontinued in 33 patients. Fifty patients had an ongoing response (CR in 41, PR in 6, and SD in 3 patients), 25 had progressed. Ten died in the follow-up, eight with progressive disease and two due to infection while in CR. The 2-year PFS and OS rates were 67.75% (95% confidence interval [CI]: 0.55-0.77) and 87.61% (95% CI: 0.76-0.94), respectively. Seventeen patients (23%) received BV in the pre-ASCT treatment lines, and there was no survival difference between the BV-naïve and BV-exposed groups. The most common adverse events were neutropenia (27%) and peripheral neuropathy (21%). Sixteen patients (21.3%) experienced grade 3 or 4 toxicity. BV was discontinued due to adverse event in 12 patients. Consolidation with BV after ASCT can achieve a 2-year PFS of 67.75% (95% CI: 0.55-0.75) with an acceptable toxicity profile.

Cytomegalovirus reactivation during adult acute lymphoblastic leukemia maintenance: do we underestimate (un)expected guest of pediatric approach?

Among acute lymphoblastic leukemia (ALL), 40% of affected patients are diagnosed after the age of 20. Compared to pediatricians, adult hemato-oncologists are less familiar with complex pediatric ALL regimens and have perceived that pediatric ALL regimens are too toxic in the adult population. Meanwhile, multiple retrospective analyzes showed the superiority of pediatric regimens among the older adults and young adolescents (AYAs) group over adult regimens. A series of prospective studies have made it apparent that pediatric-inspired ALL regimens are feasible in AYAs, with manageable toxicities and potentially more encouraging results. However, the complications in the adult population are still to be explored. Although cytomegalovirus (CMV) viremia and infections are increasingly recognized in pediatric ALL cases, we generally do not experience it frequently in adult cases with conventional strategies. Herein we represent a 38-year-old man diagnosed with ALL and treated with pediatric inspired GRAALL-2003 protocol. Following a successful induction phase, he had pancytopenia, deep lymphopenia, fever and diarrhea in the 9th month of maintenance therapy. With increased serum ferritin and triglyceride levels, he had features of macrophage activation syndrome. The bone marrow biopsy did not reveal any relapse or hemophagocytosis. We detected highly increased levels of CMV DNA (657.262 copies/mL) in blood analysis.

Nivolumab for relapsed or refractory Hodgkin lymphoma: real-life experience.

Classical Hodgkin lymphoma (cHL) is considered a curable disease; however, in approximately one-third of the responding patients, the disease relapses following completion of therapy. One of the drugs that have been approved for the treatment of relapsed/refractory cHL is nivolumab, an immune check point inhibitor that shows its effects by blocking the programmed death 1 (PD-1) receptor. In this study, we present a retrospective "real-life" analysis of the usage of nivolumab in patients with relapsed/refractory cHL that have joined the named patient program (NPP) for nivolumab, reflecting 4 years of experience in the treatment of relapsed/refractory cHL. We present a retrospective analysis of 87 patients (median age, 30) that participated in the NPP in 24 different centers, who had relapsed/refractory cHL and were consequently treated with nivolumab. The median follow-up was 29 months, and the median number of previous treatments was 5 (2-11). In this study, the best overall response rate was 70% (CR, 36%; PR, 34%). Twenty-eight of the responding patients underwent subsequent stem cell transplantation (SCT). Among 15 patients receiving allogeneic stem cell transplantation, 9 patients underwent transplantation with objective response, of which 8 of them are currently alive with ongoing response. At the time of analysis, 23 patients remained on nivolumab treatment and the rest discontinued therapy. The main reason for discontinuing nivolumab was disease progression (n = 23). The safety profile was acceptable, with only nine patients requiring cessation of nivolumab due to serious adverse events. The 24-month progression-free and overall survival rates were 58.5% (95% CI, 0.47-0.68) and 78.7% (95% CI, 0.68-0.86), respectively. Eighteen patients died during the follow-up and only one of these was regarded to be treatment-related. With its efficacy and its safety profile, PD-1 blockers became an important treatment option in the heavily pretreated cHL patients.

Bortezomib induced pulmonary toxicity: a case report and review of the literature.

Bortezomib is widely used in the treatment of Multiple Myeloma. While the most common side effects are neurological and gastrointestinal related complications, severe pulmonary problems are rarely described. The present case is a 72-year old male with multiple myeloma, who received Lenalidomide, Bortezomib, and Dexamethasone (RVD) combination regimen. He underwent 30 Gy palliative radiotherapy to the thoracic 5-9 and lumbar L1-3 vertebra due to pain and fracture risk. During the third cycle, he was admitted to hospital with dyspnea and dizziness. The thoracic CT revealed bilateral pleural effusions, a diffuse reticular pattern on the parenchyma, and ground-glass opacities that were compatible with drug-induced lung injury. The microbiological and molecular analysis excluded infectious disease, and lung biopsy confirmed the diagnosis of Bortezomib Lung Injury. The time from the first dose of Bortezomib to the lung injury was 57 days, and it was five days from the last dose of Bortezomib. His symptoms were refractory to IV steroids and supportive care. Our patient was lost despite steroids and intensive care support. Even Bortezomib induced lung injury is a rare adverse effect, based on high mortality rate, we would like to emphasize the clinical importance of this clinical scenario in light of the published literature and our presented case.

Long-term results of brentuximab vedotin in relapsed and refractory Hodgkin lymphoma: multi-center real-life experience.

Classical Hodgkin lymphoma (cHL) is considered a curable disease; however, approximately one-third of responders experience disease relapse following first-line therapy. Several studies have shown the efficacy of brentuximab vedotin (BV) in patients with relapsed/refractory HL. We present a retrospective analysis of 58 patients with relapsed/refractory HL treated with BV in a named patient program from 11 centers. The median follow-up duration was 20 (range, 4-84) months. The best overall response rate was 64% (complete response [CR], 31%; partial response [PR], 33%). The 5-year progression-free survival (PFS) and overall survival (OS) rates were 12% (95% confidence interval [CI], 0.05-0.22) and 26% (95% CI, 0.16-0.38), respectively. Among patients who achieved CR, the estimated 5-year PFS and OS rates were 32% (95% CI, 0.13-0.54) and 60% (95% CI, 0.33-0.78), respectively. A total of 26 patients underwent subsequent stem cell transplantation. The 5-year PFS and OS rates for 10 patients who had consolidative stem cell transplantation were 28% and 30%, respectively. Twenty-seven patients required further therapy following BV. At the time of the analysis, 12 patients (21%) were alive. Five patients (9%) had long-term remission after achieving CR with BV monotherapy, with a median PFS of 76 months. Three of them (5%) did not receive any other treatment following BV and their median PFS was 75 months. Our long-term results showed that a small subset of patients with relapsed/refractory cHL may benefit from and even be cured with BV monotherapy.

Inflammatory myofibroblastic tumor mimicking a relapse in a patient with Hodgkin's lymphoma: report of an unusual case and review of the literature.

New PET-positive lesions in previously treated patients with lymphomatous malignancies need further investigations. Relapse, sarcoidosis and secondary malignancies are the most important differential diagnosis. Inflammatory myofibroblastic tumors (IMT) is a rare complication after treatment of Hodgkin's disease and every PET-positive lesion should be biopsied to prevent unnecessary intervention.

Bronchus Associated Lymphoid Tissue Lymphoma Presenting with Immunodeficiency and Multiple Pulmonary Nodules.

Bronchus Associated Lymphoid Tissue Lymphoma (BALTOMA) is a rare subgroup of pulmonary non-Hodgkin's lymphomas (NHLs) comprising less than 1% of all cases. It constitutes 3.6% of all extranodal lymphomas and only 0.5-1% of primary pulmonary malignancies. They are usually low grade B-cell lymphomas and are considered to originate from the mucosa associated lymphoid tissue (MALT) of the bronchi. Here, we represent a rare case of BALTOMA presenting with immunodeficiency and multiple pulmonary nodules.

Use of fluorodeoxyglucose positron emission tomography for diagnosis of bleomycin-induced pneumonitis in Hodgkin lymphoma.

Bleomycin is an antineoplastic agent causing fatal pulmonary toxicity. Early diagnosis of bleomycin-induced pneumonitis is crucial to prevent irreversible damage. Pulmonary function tests are unreliable for identifying risk of bleomycin toxicity. Fluorodeoxyglucose PET/CT scanning can reveal inflammation secondary to pneumonitis but is not sufficiently specific for diagnosis. We retrospectively analyzed scans from 77 patients with Hodgkin lymphoma (median age 41 years, mean bleomycin dose 134 mg) to evaluate bleomycin-induced pneumonitis. We identified 13 patients with abnormal lung uptake of fluorodeoxyglucose. Tracer activity was predominantly diffuse, bilateral, in the lower lobes and subpleural areas. Interim scanning during treatment revealed pneumonitis in eight of 13 patients (asymptomatic in six). One asymptomatic patient died of bleomycin toxicity. For remaining 12 patients, bleomycin was discontinued and methylprednisolone given, all showed resolution of the pneumonitis. These findings suggest that routine interim or end-of-treatment FDG-PET/CT scanning could be beneficial for alerting clinicians to asymptomatic bleomycin-induced toxicity.

Detailed analysis of diffuse large B cell lymphoma patients: a single-center, retrospective study.

The aim of this single-center, retrospective study was to investigate the impact of rituximab, reconsider the validity of International Prognostic Index (IPI), and evaluate the prognostic role of the cell of origin (CoO) in a relatively young cohort. Three hundred twelve diffuse large B cell lymphoma patients (median age: 52) were included. Rituximab significantly improved the 3- and 5-year progression free survival (PFS) (70% versus 65% and 41% versus 36%, resp.; P < 0.001) but led only to a slight, insignificant increase in 3- and 5-year overall survival (OS) (71% versus 77.3% and %67 versus 74.5%, resp.; P = 0.264). In the young, low risk patient subgroup (aaIPI = 0&1; n = 129), rituximab improved 3- and 5-year PFS and OS rates (P < 0.001 and P = 0.048, resp.). The efficacy of rituximab in young high risk patients was comparable to the literature. CoO data were available in 190 patients. The OS at 3 years was 79% for GC and 64% for non-GC subgroups (P = 0.014). To the best of our knowledge, this is the first study which investigated the impact of R-CHOP in the context of CoO and IPI in a relatively young cohort. CoO was not an independent risk factor for prognosis in the multivariate analysis although patients with GC showed a significant survival advantage in the univariate analysis. CoO was also found to be a significant determinant of response in refractory/relapsed patients. Our results confirm the efficacy of rituximab in low and high risk, young patients outside of a randomized clinical trial setting.

Is valganciclovir really effective in primary effusion lymphoma: case report of an HIV(-) EBV(-) HHV8(+) patient.

Primary effusion lymphoma (PEL) is a human herpesvirus 8 (HHV8) associated lymphoproliferative disease characterized by effusions in body cavities, and lack of tumor mass. Valganciclovir is a treatment option in PEL, however, little is known about its clinical efficacy. Ganciclovir has been reported to be effective in HHV8(+) multicentric Castleman's disease (MCD) by decreasing the plasma HHV8 load, which is an important factor in the induction and persistence of MCD, Kaposi's sarcoma (KS), and PEL. But there is no information about the efficacy of valganciclovir on HHV8 associated lymphoproliferative diseases. Here, we present the first EBV and HIV negative, HHV8 positive PEL case treated with valganciclovir; for whom it initially reduced the viral load leading to a transient partial improvement in the clinical status, but failed to induce a complete and durable remission.

Azacitidine has limited activity in 'real life' patients with MDS and AML: a single centre experience.

Myelodysplastic syndrome (MDS) represents a heterogeneous group of potentially malignant diseases of bone-marrow stem cells. Acute myelogenous leukaemia (AML) is an inevitable outcome for many patients with MDS. Azacitidine has been reported to result in comparably higher response rates and improved survival than other treatment strategies. In this retrospective study, we report the results on 25 'real life' patients with MDS, CMML or AML treated with azacitidine between 2005 and 2009. All patients fulfilled the World Health Organization criteria for MDS and AML. No eligibility criteria other than diagnosis were considered. Complete response (CR) rate was observed in three of the 25 'real life' patients (12%) with a median duration of CR of 5 months (4-6 months). Seven patients (28%) had mono- or bi-lineage haematologic improvement and 15 patients (60%) showed neither morphologic nor haematologic response. Among 17 non-AML patients, the median time from onset of Aza-C treatment to AML transformation was 10 months (4-15 months). Overall death rate was 72%. All of the eight AML patients died. The death rate under Aza-C among non-AML patients was 59%. Unlike the results of the clinical trials, our data show that Aza-C has a limited activity in 'real-life' patients with MDS and AML. It is obvious that Aza-C can induce complete or partial responses in a considerable number of MDS patients but responses are usually not durable as we observed in our patients.