Analysis of vaccine responses after anti-CD20 maintenance in B-cell lymphoma in the Balearic Islands. A single reference center experience.

Introduction: The use of maintenance approaches with anti-CD20 monoclonal antibodies has improved the outcomes of B-cell indolent lymphomas but may lead to significant peripheral B-cell depletion. This depletion can potentially hinder the serological response to neoantigens. Methods: Our objective was to analyze the effect of anti-CD20 maintenance therapy in a reliable model of response to neoantigens: SARS-CoV-2 vaccine responses and the incidence/severity ofCOVID-19 in a reference hospital. Results: In our series (n=118), the rate of vaccination failures was 31%. Through ROC curve analysis, we determined a cutoff for SARS-CoV-2 vaccine serologic response at 24 months from the last anti-CD20 dose. The risk of severe COVID-19 was notably higher within the first 24months following the last anti-CD20 dose (52%) compared to after this period (just 18%) (p=0.007). In our survival analysis, neither vaccine response nor hypogammaglobulinemia significantly affected OS. While COVID-19 led to a modest mortality rate of 2.5%, this figure was comparable to the OS reported in the general immunocompetent population. However, most patients with hypogammaglobulinemia received intravenous immunoglobulin therapy and all were vaccinated. In conclusion, anti-CD20 maintenance therapy impairs serological responses to SARS-CoV-2 vaccines. Discussion: We report for the first time that patients during maintenance therapy and up to 24 months after the last anti-CD20 dose are at a higher risk of vaccine failure and more severe cases of COVID-19. Nevertheless, with close monitoring, intravenous immunoglobulin supplementation or proper vaccination, the impact on survival due to the lack of serological response in this high-risk population can be mitigated, allowing for the benefits of anti-CD20 maintenance therapy, even in the presence of hypogammaglobulinemia.

The International Prognostic Index Is Associated with Outcomes in Diffuse Large B Cell Lymphoma after Chimeric Antigen Receptor T Cell Therapy.

CD19-targeted chimeric antigen receptor (CAR) T cells have shown excellent activity against relapsed and refractory (R/R) diffuse large B cell lymphoma (DLBCL). CAR T cell therapy is associated with early toxicities, including cytokine release syndrome and neurotoxicity. The incidence and severity of these toxicities has been associated in part with baseline disease and patient characteristics, which also may impact overall survival (OS) and progression-free survival (PFS). However, there are limited data on patient selection and how to better predict toxicities or outcomes. Indexes used in patients with DLBCL, such as the International Prognostic Index (IPI and age-adjusted IPI [aaIPI]) and in transplantation recipients, such as the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI), have not been evaluated in this setting. Here we evaluated 4 indices- IPI, aaIPI, HCT-CI, and the Charlson Comorbidity Index (CCI)-and their associations with early CAR T cell related-toxicities and outcomes. We demonstrated an association between high-risk IPI or aaIPI and inferior PFS in patients with R/R DLBCL treated with CAR T cell therapy. We also found an association between aaIPI and IPI with OS and neurotoxicity, respectively. CCI was not associated with toxicities or outcomes, and owing to the small sample size, we could not draw a conclusion regarding associations with the HCT-CI. Both the IPI and aaIPI are widely used tools that can now provide better information to guide selection of patients who would best benefit from CD19 CAR T cell therapy.

Infection during the first year in patients treated with CD19 CAR T cells for diffuse large B cell lymphoma.

CD19-targeted chimeric antigen receptor (CAR) T cell therapy is an effective treatment for diffuse large B cell lymphoma (DLBCL). In addition to cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS), B cell aplasia and hypogammaglobulinemia are common toxicities predisposing these patients to infections. We analyzed 60 patients with DLBCL treated with FDA-approved CD19 CAR T cells and report the incidence, risk factors, and management of infections during the first year after treatment. A total of 101 infectious events were observed, including 25 mild, 51 moderate, 23 severe, 1 life-threatening, and 1 fatal infection. Bacteria were the most common causative pathogens. The cumulative incidence of overall, bacterial, severe bacterial, viral, and fungal infection at 1 year were 63.3%, 57.2%, 29.6%, 44.7%, and 4%, respectively. In multivariate analyses, the use of systemic corticosteroids for the management of CRS or ICANS was associated with an increased risk of infections and prolonged admission. Impaired performance status and history of infections within 30 days before CAR T cell therapy was a risk factor for severe bacterial infection. In conclusion, infections were common within the first 60 days after CAR T cell therapy, however, they were not associated with an increased risk of death.

DLBCL patients treated with CD19 CAR T cells experience a high burden of organ toxicities but low nonrelapse mortality.

Cytokine release syndrome (CRS) immune effector cell-associated neurotoxicity syndrome are the most notable toxicities of CD19 chimeric antigen receptor (CAR) T-cell therapy. In addition, CAR T-cell-mediated toxicities can involve any organ system, with varied impacts on outcomes, depending on patient factors and involved organs. We performed detailed analysis of organ-specific toxicities and their association with outcomes in 60 patients with diffuse large B-cell lymphoma (DLBCL) treated with CD19 CAR T cells by assessing all toxicities in organ-based groups during the first year posttreatment. We observed 539 grade ≥2 and 289 grade ≥3 toxicities. Common grade ≥3 toxicities included hematological, metabolic, infectious, and neurological complications, with corresponding 1-year cumulative incidence of 57.7%, 54.8%, 35.4%, and 18.3%, respectively. Patients with impaired performance status had a higher risk of grade ≥3 metabolic complications, whereas elevated lactate dehydrogenase was associated with higher risks of grade ≥3 neurological and pulmonary toxicities. CRS was associated with higher incidence of grade ≥3 metabolic, pulmonary, and neurologic complications. The 1-year nonrelapse mortality and overall survival were 1.7% and 69%, respectively. Only grade ≥3 pulmonary toxicities were associated with an increased mortality risk. In summary, toxicity burdens after CD19 CAR T-cell therapy were high and varied by organ systems. Most toxicities were manageable and were rarely associated with mortality. Our study emphasizes the importance of toxicity assessment, which could serve as a benchmark for further research to reduce symptom burdens and improve tolerability in patients treated with CAR T cells.

Evaluation of the MD Anderson tumor score for diffuse large B-cell lymphoma in the rituximab era.

OBJECTIVES: Diffuse large B-cell lymphoma (DLBCL) is an aggressive heterogeneous lymphoma with standard treatment. However, 30%-40% of patients still fail, so we should know which patients are candidates for alternative therapies. IPI is the main prognostic score but, in the rituximab era, it cannot identify a very high-risk (HR) subset. The MD Anderson Cancer Center reported a score in the prerituximab era exclusively considering tumor-related variables: Tumor Score (TS). We aim to validate TS in the rituximab era and to analyze its current potential role. METHODS: From GELTAMO DLBCL registry, we selected those patients homogeneously treated with R-CHOP (n = 1327). RESULTS: Five-years PFS and OS were 62% and 74%. All variables retained an independent prognostic role in the revised TS (R-TS), identifying four different risk groups, with 5-years PFS of 86%, 71%, 50%, and very HR (28%). With a further categorization of three variables of the original TS (Ann Arbor Stage, LDH and B2M), we generated a new index that allowed an improvement in HR assessment. CONCLUSIONS: (a) All variables of the original TS retain an independent prognostic role, and R-TS remains predictive in the rituximab era; (b) R-TS and additional categorization of LDH, B2M, and AA stage (enhanced TS) increased the ability to identify HR subsets.

Comparative Cost Analysis Of Intravenous And Subcutaneous Administration Of Rituximab In Lymphoma Patients.

PURPOSE: The availability of different routes of administration of rituximab, with different dosing and times of infusion in the day care unit, raises the question of which formulation would be the best in terms of direct cost, particularly with the approval of new intravenous (IV) rituximab biosimilars. We aim to retrospectively compare the direct costs of IV and subcutaneous (SC) rituximab in lymphoma, considering drug cost, pharmacy handling and occupation in day care unit in Son Espases University Hospital during 2017, now that the IV biosimilar is available. PATIENTS AND METHODS: The data were collected from Oncosafety®-AVIDA for doses and SAP® for economic data. The costs of occupation are published by the Local Health Service. RESULTS: In 2017, 527 cycles were prescribed for 103 patients with lymphoma: 141 IV and 386 SC. Median doses were 690 mg and 1400 mg with a median cost of the drug of 1458.45€ and 1334.77€ for IV and SC routes, respectively. The nurse handling costs were 4.49€ and 2.24€, respectively. The cost of the day care unit occupation was 493€ and 123€, respectively. Overall, the median total cost per cycle was 1955.94€ for the IV, 1460.01€ for the SC and 1729€ for the biosimilar (p<0.001). The sensitivity analysis showed that it would be necessary for the cost of the IV biosimilar to be 34% lower than the price of SC rituximab to make a difference. CONCLUSION: This study shows a reduction in the cost with the administration of SC rituximab in real life compared with using the IV original rituximab and the biosimilar. This information is relevant for healthcare managers and administrations and applies only in the case of drugs with SC original presentations still not available in their correspondent biosimilars.

Use and safety of riboflavin and UV light-treated platelet transfusions in children over a five-year period: focusing on neonates.

BACKGROUND: There are very few published reports about the use and safety of pathogen reduction technology (PRT) based on riboflavin and UV light for platelet (PLT) transfusion in children. STUDY DESIGN AND METHODS: A two-part study was conducted: 1) a study investigating the safety of PLTs treated with riboflavin and UV light-PRT transfused to 379 children and 1,980 adults over a 5-year period; 2) an observational study evaluating the efficacy of PLT use in 132 neonates transfused with PRT-treated PLT compared with 99 neonates receiving standard PLTs over two 5-year periods. RESULTS: The rate of adverse reactions related to transfusions with PRT-treated PLTs was found to be slightly higher in adults than in children, although not statistically significant (0.19% vs. 0.12%; p = 0.85). All PLT transfusion events in children were mild. From 2013 to 2017, 379 children received 4,236 riboflavin and UV light-treated PLTs. Hemato-oncology patients received the most PLT transfusions (61.2%), followed by critically ill children in the Pediatric Intensive Care Unit (PICU) (24.6%), and neonates in the Neonatal Intensive Care Unit (NICU) (10.5%). A significant increase in PLT transfusions was found in 132 neonates transfused with 458 PRT-treated PLTs compared with 99 neonates receiving 176 standard PLTs, measuring PLT use/patient (p = 0.031) and total PLT dose/patient (p = 0.041). CONCLUSIONS: Riboflavin and UV light-based PRT for PLTs seems to be safe for children. Neonates required a higher number of PLT transfusions when these were PRT-treated rather than standard. A long-term follow-up for chronically transfused children and randomized clinical trials are needed.

Rhabdomyosarcoma debut masquerading as acute lymphoblastic leukemia: A case report and review of the literature.

Bone marrow infiltration by alveolar rhabdomyosarcoma is uncommon, some cases can mimicry acute leukemia at presentation and mislead the diagnosis. The integration of diagnostics tests and techniques in uncommon malignancies is important to suspect and reach the diagnosis and avoid delay on treatment. We report a case of alveolar rhabdomyosarcoma bone marrow infiltration associated with hemophagocytosis and cell cannibalism, mimicking acute leukemia at presentation.

Complete response associated with lenalidomide and celecoxib in a case of primary refractory Hodgkin lymphoma.

Hodgkin lymphoma (HL) represents ~11% of all lymphoma cases. This disease occurs in young adults, but also affects people over 55 years of age. Despite the fact that >80% of all newly diagnosed patients under 60 will achieve a sustained complete response (CR), 5%-10% of HL patients are refractory to initial treatment and 10%-30% of patients will eventually relapse after an initial CR. The treatment recommendation for primary refractory or relapsed HL patients is salvage therapy followed by high-dose chemotherapy and autologous stem cell transplantation. Following this approach, a significant part will still relapse at any moment. Thus, further research and new drugs or combinations are required. Overexpression of COX-2 has been associated with poor prognosis in relapse/refractory HL patients, so it could be a potential therapeutic target in HL. For this purpose, several drugs may have a role: specific COX-2 inhibitors such as celecoxib or other anti-inflammatory drugs such as lenalidomide may further inhibit lipopolysaccharide-mediated induction of COX-2. Moreover, lenalidomide and COX-2 inhibitors (celecoxib) have been tested in solid tumors with encouraging results. We present a case of a young female diagnosed with a heavily pretreated HL nodular sclerosis subtype who, after failing six treatment lines, only achieved clinical and radiological CR after six cycles of lenalidomide/celecoxib that resulted in an event-free survival of 22 months. We explain the rationale of using this chemotherapy regimen and our patient follow-up.

Our experience in riboflavin and ultraviolet light pathogen reduction technology for platelets: from platelet production to patient care.

BACKGROUND: Pathogen reduction technology (PRT) enhances blood component safety, but its implementation is hampered by loss of blood quality and cost. STUDY DESIGN AND METHODS: A retrospective study was conducted to investigate the efficacy, safety, and cost of 9673 riboflavin and ultraviolet light-treated platelet (PLT) transfusions given to 1211 patients during a 3-year period. The results were compared with the efficacy, safety, and cost of 6424 nontreated PLT transfusions administered to 1500 patients during a 3-year comparison period before PRT implementation. RESULTS: Despite a similar PLT transfusion dose per unit for both periods (pre-PRT period 3.26 vs. PRT period 3.19), the mean number of PLT concentrates per patient (4.2 vs. 7.8; p = 0.006) and the total dose of PLTs received by patients were higher in the PRT period (13.6 vs. 24.8; p = 0.0002). Hematology and medical and surgical patient categories had the highest PLT use per patient. However, febrile (2.5% vs. 1.2%; p = 0.02) and allergic (0.16% vs. 0.08%; p = 0.01) reactions were lower during the PRT period. The blood center saved €284,805.58 due to a reduction of outdated PLTs from 16.8% to 0.72% after PRT implementation. CONCLUSIONS: Although PRT can improve PLT safety, it can increase the amount of PLTs required for transfusion in some patient categories. The cost of PRT can be partially offset by the savings associated with a lower rate of PLT outdates. This cost reduction can be a key factor in settings where inventory management is challenged by a high percentage of wasted PLTs due to outdating.

Analysis of the role of intratecal liposomal cytarabine in the prophylaxis and treatment of central nervous system lymphomatosis: The Balearic Lymphoma Group experience.

Central nervous system (CNS) lymphomatosis is a fatal complication of aggressive non-Hodgkin lymphoma (NHL). In lymphoblastic or Burkitt lymphoma, without specific CNS prophylaxis the risk of CNS relapse is 20-30%. DLBCL has a lower risk of relapse (around 5%) but several factors increase its incidence. There is no consensus or trials to conclude which is the best CNS prophylaxis. Best results seem to be associated with the use of intravenous (iv) high-dose methotrexate (HDMTX) but with a significant toxicity. Other options are the administration of intrathecal (IT) MTX, cytarabine or liposomal cytarabine (ITLC). Our aim is to analyze the experience of the centers of the Balearic Lymphoma Group (BLG) about the toxicity and efficacy of ITLC in the prophylaxis and therapy of CNS lymphomatosis. We retrospectively reviewed cases from 2005 to 2015 (n = 58) treated with ITLC. Our toxicity results were: 33% headache, 20% neurological deficits, 11% nausea, 9% dizziness, 4% vomiting, 4% fever, 2% transient blindness and 2% photophobia. In the prophylactic cohort (n = 26) with a median follow-up of 55 months (17-81) only 3 CNS relapses (11%) were observed (testicular DLBCL, Burkitt and plasmablastic lymphoma, with a cumulative incidence of 8%, 14% and 20% respectively). In the treatment cohort (n = 32), CSF complete clearance was obtained in 77% cases. Median OS was 6 months (0-16). Death causes were lymphoma progression (19 patients, 79%), treatment toxicity (2 patients) and non-related (3 patients, 12%). Toxicity profile was good especially when concomitant dexamethasone was administered. In the prophylactic cohort the incidence of CNS relapse in DLBCL group was similar to previously reported for HDMTX and much better than IT MTX. A high number of ITLC injections was associated with better rates of CSF clearance, clinical responses, PFS and lower relapses. Survival is still poor in CNS lymphomatosis and new therapeutic approaches are still needed.

Lenalidomide, celecoxib, and azacitidine therapy for blastic plasmocytoid dendritic cell neoplasm: a case report.

Blastic plasmocytoid dendritic cell neoplasm is characterized by aggressive behavior with a tendency for systemic dissemination and a predilection for skin, lymph nodes, soft tissues, peripheral blood, or bone marrow. It usually occurs in elderly patients with a mean age between 60 and 70 years. Despite initial response to chemotherapy, the disease regularly relapses with a short median overall survival. Better outcomes have been reported with high-dose acute leukemia-like induction chemotherapy followed by consolidation with allogeneic hematopoietic stem cell transplantation. However, elderly patients are not candidates for intensive therapy or allogeneic stem cell transplantation. So, new active and tolerable drugs are needed. Our case illustrates that one cycle of lenalidomide and celecoxib provides at least a partial cutaneous and hematologic response, but this regimen was discontinued due to toxicity and followed by a consolidation/maintenance phase with azacitidine, thus achieving a final complete response with a much higher than expected progression-free and overall survival in an elderly patient with comorbidities. This information may be useful in the design of treatment approaches for elderly patients with blastic plasmocytoid dendritic cell neoplasm. However, it should be confirmed in clinical trials as well as by optimizing the induction and extending the consolidation/maintenance period to avoid early relapses after discontinuation and improve progression-free survival.

Efficacy of the GemOx-R regimen leads to the identification of Oxaliplatin as a highly effective drug against Mantle Cell Lymphoma.

Mantle Cell Lymphoma (MCL) is an aggressive lymphoma subtype that accounts for 6-8% of non-Hodgkin lymphomas. The disease is mostly incurable and characterized by a continuous pattern of relapse. Major changes have recently been implemented in the management of MCL, but continuous relapses still mark this disease as a challenge for clinicians. We previously reported the efficacy of GemOx-R (Gemcitabine, Oxaliplatin and Rituximab) in patients with refractory and relapsing MCL. We present results for a larger series with longer follow-up and including high-risk frontline patients, showing an overall response rate of 83%. The efficacy of each component of GemOx-R was evaluated in a panel of MCL cell lines. Also, patient-derived primary cells were used in ex vivo experiments. The results show that oxaliplatin has a profound effect on cellular viability and is the most effective drug within this regimen. We further present synergistic efficacy of oxaliplatin combined with cytarabine in MCL cells. Interestingly, this synergistic effect was not seen when cisplatin and cytarabine were combined, indicating that among the platinum-derived agents oxaliplatin may be the preferred approach. Taken together our findings suggest that oxaliplatin alone or combined with cytarabine could constitute an alternative backbone for MCL regimens.