Response to therapy in Richter syndrome: a systematic review with meta-analysis of early clinical trials.

Introduction and aims: Richter syndrome (RS) represents the clonal evolution of chronic lymphocytic leukemia with histological transformation into a high-grade B cell lymphoma (diffuse large B cell lymphoma - DLBCL) or Hodgkin lymphoma. Considering that RS is an uncommon condition with poor prognosis, few high-quality evidence is available. To overcome this unmet need, this meta-analysis aimed to pool efficacy of early clinical trials in Richter syndrome (DLBCL subtype). Methods: MEDLINE, Scopus and Web of Science were searched up to May of 2023 to identify clinical trials decoying efficacy. The pooled complete response, objective response and intension-to-treat failure rates were calculated by pharmacological categories (classical chemotherapy, immunochemotherapy, immunotherapy, Bruton-tyrosine kinase inhibitors, targeted approaches, cell-based therapies and combinatorial regimens) using the Der-Simonian and Laird random-effects model. The Freeman-Tukey double arcsine method was used to estimate variance and confidence intervals. Heterogeneity was assessed using the I2 method. Results: Overall, from 1242 studies identified, 30 were included, pooling data from 509 patients. The higher efficacy rates when, cell-based therapies were excluded, were achieved by immunochemotherapeutic regimens followed by combinatorial regimens, with complete response rates of 21.54% (IC95%14.93-28.87) and 23.77% (IC95% 8.70-42.19), respectively. Bispecific antibodies (alone or coupled with a chemotherapy debulking strategy) overtook Bruton tyrosine kinase inhibitors response rates. The latter, although achieving objective response rates above average, presented scarce complete response rates. Checkpoint inhibitors alone usually do not lead to complete responses, but their effectiveness may improve when combined with other agents, unveiling the importance of immune microenvironmental modulation. Conclusion: This is the first meta-analysis of early clinical trials assessing the impact of different therapeutics in RS. By analyzing the pooled efficacy estimates, our work suggests the role of a tailor-made bridging therapy for young patients with RS eligible for allogeneic hematopoietic stem cell transplantation (alloSCT), formally the only curative strategy.

Costs, effectiveness, and safety associated with Chimeric Antigen Receptor (CAR) T-cell therapy: Results from a comprehensive cancer center.

Real world effectiveness, toxicity and costs analyses from chimeric antigen receptor (CAR)-T cell therapy are of utmost relevance to determine whether and how to offer patients highly personalized immunotherapy. In this study, we aimed at describing CAR T-cells effectiveness, safety and costs in a Portuguese Comprehensive Cancer Center. We performed a retrospective descriptive study of adult patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma and transformed follicular lymphoma referred to CAR T-cell therapy, between May 2019 and February 2021. Rates of treatment response, toxicity and survival (Kaplan-Meier method) were analyzed by intention-to-treat. Direct medical costs stratified by inpatient-care, outpatient-care, and diagnostic-therapeutic procedures (DTP) were derived based on resources used and their respective unit costs. In twenty patients (median age 49.5y; 55%male; 70%DLBCL; 50% with primary refractory disease), best overall and complete response rates were 65.0% and 45.0%, respectively. Median overall (OS) and progression-free survivals were 9.2 and 7.3 months; 12-month OS rate was 42.6% (95%CI:23.2-78.3). Grade≥3 cytokine release syndrome and neurotoxicity occurred in 5.6% and 11.1% of patients, respectively. CAR T-cell therapy expenditure, including adverse events costs, was 7 176 196€, or 286 238€ when excluding drug cost. Median cost for treated patient was 355 165€ with CAR T-cell drug cost accounting for 97.0% of the overall expense. Excluding CAR T-cell acquisition cost, inpatient-care and DTP accounted for 57% and 38% of total cost/patient, respectively. Our findings highlight the heavy economic burden of CAR T-cell therapy driven by drug acquisition costs.

Ultra-low dose radiotherapy in the management of low-grade orbital lymphomas.

Background: Ultra-low dose radiotherapy (ULDRT) (2 × 2 Gy) has been used for symptomatic control of low-grade lymphomas with surprising local control rates, suggesting that these entities could respond to lower doses. These are particularly desirable for the treatment of orbital sites and some publications refer to high rates of complete responses. In this paper, we present our experience with the use of ULDRT for indolent orbital lymphomas. Materials and methods: Electronic files and treatment plans of patients treated with ULDRT for low-grade orbital lymphoma were retrospectively reviewed. Oncological outcomes and toxicities were collected and described for each patient. Results: Seven patients (median age of 75 years) with 8 lesions (3 follicular, 2 MALT, 1 marginal and 1 low-grade non-Hodgkin lymphoma) were considered for analysis. The majority had stage IE disease and one patient had bilateral disease. Six tumors were detected on imaging (median size of 20 mm). Involved orbital sites were periocular, conjunctival and palpebral; there was one case of intraocular (choroid) and one case of lacrimal gland involvement. One patient received consolidative rituximab after RT. The median follow-up time was 22 months. Two patients had partial response, one of them with persistent minimal choroidal disease and the other with partial response on CT. Five (71%) patients had clinical (n = 2) or radiologic (n = 3) complete response on treated sites. Reported late toxicities were minimal and included dry eye and pruritus. Conclusion: In our experience, ULDRT achieved a local control rate of 100% and complete response rate of 71% with minimal toxicity.

IgA nephropathy in IgG kappa multiple myeloma.

Multiple myeloma (MM) frequently affects kidney function through multiple mechanisms. Nonetheless, some patients develop kidney injury due to other causes. A 54-year-old woman was diagnosed with IgG kappa MM developed IgA nephropathy without cast nephropathy. Further studies did not show criteria for MM progression or other causes. This case highlights the need for further investigation of kidney injury in MM patients (such as toxicity of previous drugs, infectious events, or immune-mediated disorders).

Management of ibrutinib treatment in patients with B-cell malignancies: clinical practice in Portugal and multidisciplinary recommendations.

OBJECTIVES: Ibrutinib, a potent inhibitor of the Bruton tyrosine kinase, has revolutionized the treatment of many B-cell malignancies. Ibrutinib has an established favorable toxicity profile with up to 8 years of experience in clinical trials; however, despite ibrutinib's favorable toxicity profile, dose reductions and treatment discontinuations are becoming more evident in clinical practice, particularly in the setting of specific clinical contexts and patient characteristics. This manuscript is set to provide practical recommendations on the management of patients treated with this agent in daily practice. METHODS: A group of multidisciplinary experts from Portugal met to discuss and highlight practical recommendations, supported on both literature and clinical insights, for the management of the treatment with ibrutinib. RESULTS/DISCUSSION: Handling of both toxicities and drug-drug interactions during ibrutinib treatment poses several challenges to healthcare providers and can benefit from a multidisciplinary approach. The involvement of specialties, such as cardiology, infectiology and pharmacology, can bring an added value to patient care, not only in anticipating/managing safety issues and dose adjustments but also in enhancing adherence to treatment, ultimately improving the risk/benefit balance. CONCLUSION: By involving a multidisciplinary group of experts, this work provides a set of key recommendations to optimize care and outcomes for ibrutinib-treated patients. Despite not being a fully comprehensive review on the topic, it is intended as a framework to hematologists and other healthcare professionals who manage these patients in their daily clinical practice.

Disseminated Saprochaete capitata fungal infection in a patient with acute myeloid leukemia.

The case highlights the importance of actively obtaining informative samples at an early stage and of prompt initiation of combination therapy with antifungal drugs.

Successful treatment of refractory chylous ascites due to follicular lymphoma with very low-dose radiotherapy.

Chylous ascites is an extremely rare complication of lymphoma. Here, we discuss the case of a patient presenting with refractory chylous ascites due to a massive retroperitoneal follicular lymphoma, staged as IVB. The patient was unresponsive to chemoimmunotherapy, which prompted us to consider alternative treatment strategies. Low-dose radiotherapy was initiated and resulted in a marked decrease of the lymphadenopathy and complete regression of the peritoneal fluid. Low-dose radiotherapy represents a well-tolerated, highly effective treatment and should remain an important modality in cases of follicular lymphoma-associated chylous ascites.

Effect of therapy-related acute myeloid leukemia on the outcome of patients with acute myeloid leukemia.

Therapy-related acute myeloid leukemia (t-AML) is a rare and almost always fatal late side effect of antineoplastic treatment involving chemotherapy, radiotherapy or the two combined. The present retrospective study intended to characterize t-AML patients that were diagnosed and treated in a single referral to an oncological institution in North Portugal. Over the past 10 years, 231 cases of AML were diagnosed and treated at the Portuguese Institute of Oncology of Porto, of which 38 t-AML cases were identified. Data regarding the patient demographics, primary diagnosis and treatment, age at onset of therapy-related myeloid neoplasm, latency time of the neoplasm, cytogenetic characteristics, AML therapy and outcome were collected from medical records. A previous diagnosis with solid tumors was present in 28 patients, and 10 patients possessed a history of hematological conditions, all a lymphoproliferative disorder. Breast cancer was the most frequent solid tumor identified (39.5% of all solid tumors diagnosed). The mean latency time was 3 years. In the present study, t-AML patients were older (P<0.001) and more frequently carried cytogenetic abnormalities (P=0.009) compared with de novo AML patients. The overall survival time was observed to be significantly poorer among individuals with t-AML (P<0.001). However, in younger patients (age, <50 years) there was no difference between the overall survival time of patients with t-AML and those with de novo AML (P=0.983). Additionally, patients with promyelocytic leukemia possess a good prognosis, even when AML occurs as a secondary event (P=0.98). To the best of our knowledge, the present study is the first to evaluate t-AML in Portugal and the results are consistent with the data published previously in other populations. The present study concludes that although t-AML demonstrates a poor prognosis, this is not observed among younger patients or promyelocytic leukemia patients.

Diagnosis, complications and management of chronic neutrophilic leukaemia: A case report.

Chronic neutrophilic leukemia (CNL) is a rare myeloproliferative neoplasm characterized by sustained neutrophilia and the absence of the Philadelphia chromosome or the BCR-ABL1 fusion gene. The present study reports the case of a 59-year-old Caucasian female that was referred to The Francisco Gentil Portuguese Institute of Oncology (Porto, Portugal) with constitutional symptoms (mainly asthenia), marked leukocytosis (51.33×109/l with 90% neutrophils), macrocytic anemia and splenomegaly. Bone marrow aspiration and biopsy revealed hypercellular marrow with clear predominance of segmented neutrophils. The karyotype was normal and the BCR-ABL1 fusion gene was not detected. After excluding a leukemoid reaction, a diagnosis of CNL was established. The clinical follow-up was complicated by hemorrhagic brain lesions and relapsing episodes of erythematous, well-demarcated and painful subcutaneous nodular lesions, consistent with Sweet's syndrome (SS). Multiple treatment strategies were administered, including use of hydroxyurea, imatinib and intensive chemotherapy. Nevertheless, progression was documented and the patient succumbed at 28 months post-diagnosis. The clinical course of CNL varies, and can be complicated by cerebral hemorrhage, blastic transformation or infection. Dermatological manifestations such as SS have seldom been reported in association. No evidence-based treatment currently exists and the majority of our knowledge is based on results from case reports and small series.

Posterior Reversible Encephalopathy Syndrome in Children With Hematologic Malignancies.

Since its original description 2 decades ago, posterior reversible encephalopathy syndrome has been reported in children with several predisposing conditions. Epidemiologic data of posterior reversible encephalopathy syndrome in children with hematologic malignancies is still scarce. Herein, we describe the clinical and radiologic features along with the outcome and follow-up of posterior reversible encephalopathy syndrome complicating the treatment of children with hematologic malignancies. Ten patients with a median age of 6.3 years were diagnosed with posterior reversible encephalopathy syndrome. Six of them were undergoing chemotherapy and the remaining 4 were at 37, 52, 78, and 857 days after allogenic hematopoietic stem cell transplant. The median follow-up was 27.6 months. Even though follow-up imaging showed complete resolution of abnormalities in those 10 children, 2 developed secondary epilepsy. Despite accurate diagnosis of posterior reversible encephalopathy syndrome and immediate intervention, neurologic sequelae may still develop. Thus, a close follow-up should be considered in all patients.

Secondary hemophagocytic syndrome: the importance of clinical suspicion.

Hemophagocytic syndrome is a rare and potentially fatal disorder characterized by pathological immune activation associated with a primary familial disorder, genetic mutations, or occurring as a sporadic condition. The latter can be secondary to infections, malignancies, or autoimmune diseases. Clinically, patients present signs of severe inflammation, with unremitting fever, cytopenias, spleen enlargement, phagocytosis of bone marrow elements, hypertriglyceridemia, and hypofibrinogenemia. Increased suspicion is determinant to timely initiate treatment in an attempt to alter the natural history. The authors present three clinical cases of this syndrome, with a brief review of the diagnostic criteria and treatment.

Mucositis care in acute leukemia and non-Hodgkin lymphoma patients undergoing high-dose chemotherapy.

PURPOSE: This study intends to provide new insights into the incidence and care of mucositis by the epidemiological characterization of patients with hematological malignancy treated at our institution. It also aims to understand the effectiveness of several treatments used. METHODS: This is a longitudinal observational single-center study-convenience sample-which includes malignant hematologic inpatients submitted to high-dose CT from February to August 2012. We registered epidemiological data, diagnosis, oral mucositis daily questionnaire (OMDQ), World Health Organization (WHO) oral toxicity scale, and supportive medications used for mucositis. RESULTS: We evaluated 30 patients who had 73 episodes of hospitalization, having recorded the development of mucositis in 21.9 % (n = 16) episodes (22 patients with acute leukemia (AL) and 8 patients with non-Hodgkin lymphoma (NHL)). Grades 3-4 mucositis was reported in 4.1 % of the total episodes. The results of OMDQ showed some limitations in the quality of life, of patients with mucositis, related with the ability to eat and drink due to mouth pain (p < 0.001). In patients with NHL and AL, neutropenia entails an increased risk of mucositis (p < 0.001). Patients who did not initiate early prophylaxis with conservative measures developed mucositis earlier (p < 0.05). CONCLUSIONS: The incidence of mucositis is high, being reported mainly in AL patients, with limitations in quality of life. Grade 4 neutropenia increases mucositis risk. Early prophylaxis with basic oral care may delay mucositis. Further studies are crucial to characterize mucositis epidemiology, physiopathology, and its management.

What determines therapeutic choices for elderly patients with DLBCL? Clinical findings of a multicenter study in Portugal.

BACKGROUND: Age is a negative prognostic factor in lymphomas, and elderly patients are often undertreated because of toxicity concerns. The pattern of treatment in elderly patients with diffuse large B-cell lymphoma (DLBCL) in Portugal has not been previously described. PATIENTS AND METHODS: We conducted a multicenter retrospective study including 378 elderly patients with DLBCL receiving alkylating agent-containing regimens between 2003 and 2010. We compared the outcome of patients aged 60 to 79 years with patients > 79 years and analyzed the second group according to treatment. RESULTS: R-CHOP (rituximab, cyclophosphamide, doxorubicin [hydroxydaunorubicin], vincristine [Oncovin], prednisolone) was prescribed in only 60% of patients and was prescribed significantly less in patients > 79 years, despite no significant differences being found in comorbidities between the 2 age groups. Similarly, dose reductions frequently were instituted because of chronologic age and not always because of toxicity. When different regimens were compared, multivariate analysis showed an independent beneficial effect of R-CHOP in treatment outcomes. Additionally, treatment with anthracyclines and rituximab predicted a better progression-free survival (PFS) and time to progression (TTP) in patients > 79 years. CONCLUSION: This was the first characterization of the clinical care of elderly Portuguese patients with DLBCL. We showed that R-CHOP is effective even in patients > 79 years, emphasizing that treatment decisions based on age alone can compromise treatment efficacy and outcome in fit patients.

Review of therapy for relapsed/refractory multiple myeloma: focus on lenalidomide.

PURPOSE OF REVIEW: Multiple myeloma is a malignant neoplasm of plasma cells, for which there is no known cure. This article examines the efficacy and tolerability of lenalidomide, a potent structural analogue of thalidomide, for second-line treatment of patients with relapsed multiple myeloma. RECENT FINDINGS: Lenalidomide, a thalidomide analogue, was designed to provide increased efficacy, while avoiding the adverse effects associated with thalidomide therapy. Studies assessing lenalidomide as second-line therapy for multiple myeloma have shown promising beneficial effects. Lenalidomide-dexamethasone is associated with significantly longer median time to disease progression and overall survival, as well as a significantly higher proportion of patients who respond to treatment compared with dexamethasone alone. Lenalidomide (with dexamethasone) was associated with a high rate of myelosuppression in clinical trials; neutropenia, infection, thrombocytopenia, and venous thromboembolism were common grade 3-4 adverse events. However, appropriate management of these adverse events maximizes the clinical benefit of lenalidomide. SUMMARY: Lenalidomide in combination with dexamethasone is approved by the US Food and Drug Administration and the European Medicines Agency for the second-line treatment of patients with multiple myeloma. Lenalidomide is recommended as a treatment option for patients with multiple myeloma in both United States and European treatment guidelines.