Treatment Of Lymphoproliferative Disorders Research Articles

Beyond Chemotherapy: Present and Future Perspectives in the Treatment of Lymphoproliferative Disorders.

Over the past three decades, the treatment of lymphoproliferative disorders has undergone profound changes, notably due to the increasing availability of innovative therapies with the potential to redefine clinical management paradigms. A major impact is related to the development of monoclonal antibodies, checkpoint inhibitors, bispecific antibodies, and chimeric antigen receptor T (CAR-T) cell therapies. This review discusses the current landscape of clinical trials targeting various hematological malignancies, highlighting promising early-phase results and strategies to overcome resistance. Lymphoproliferative disorders encompass a range of conditions: while in Hodgkin lymphoma (HL) the goal is to reduce chemotherapy-related toxicity by integrating immunotherapy into the frontline setting, peripheral T cell lymphoma (PTCL) lacks effective targeted therapies. The review emphasizes a shifting therapeutic landscape towards precision medicine and treatment modalities that are less toxic yet more effective.

The role of EBV in haematolymphoid proliferations: emerging concepts relevant to diagnosis and treatment.

Epstein-Barr virus (EBV) is a ubiquitous gammaherpesvirus with >90% of the adult population worldwide harbouring latent infection. A small subset of those infected develop EBV-associated neoplasms, including a range of lymphoproliferative disorders (LPD). The diagnostic distinction of these entities appears increasingly relevant as our understanding of EBV-host interactions and mechanisms of EBV-driven lymphomagenesis improves. EBV may lower the mutational threshold for malignant transformation, create potential vulnerabilities related to viral alteration of cell metabolism and allow for improved immune targeting. However, these tumours may escape immune surveillance by affecting their immune microenvironment, limiting viral gene expression or potential loss of the viral episome. Methods to manipulate the latency state of the virus to enhance immunogenicity are emerging as well as the potential to detect so-called 'hit and run' cases where EBV has been lost. Finally, measurement of EBV DNA remains an important biomarker for screening and monitoring of LPD. Methods to distinguish EBV DNA derived from virions during lytic activation from latent, methylated EBV DNA present in EBV-associated neoplasms may broaden the utility of this testing, particularly in patients with compromised immune function. We highlight some of these emerging areas relevant to the diagnosis and treatment of EBV-associated LPD with potential applicability to other EBV-associated neoplasms.

Dermatitis flagelada en paciente VIH positivo con linfoma de Hodgkin

La dermatitis flagelada es una reacción cutánea que se asocia frecuentemente al uso de medicamentos como la bleomicina, un agente quimioterapéutico utilizado en el tratamiento de los trastornos linfoproliferativos y de los tumores de células germinales. La incidencia de la dermatitis flagelada varía entre el 8% y el 22% en la población mundial que recibe bleomicina; sin embargo, se desconocen los datos de prevalencia e incidencia en pacientes VIH positivos. Se presenta un paciente VIH positivo con linfoma de Hodgkin, quien consultó por aparición de lesiones cutáneas relacionadas con el inicio del tratamiento con bleomicina.

Reynoutria Japonica from Traditional Chinese Medicine: A Source of Competitive Adenosine Deaminase Inhibitors for Anticancer.

Adenosine deaminase (ADA) is an important enzyme in purine metabolism and is known as a potential therapeutic target for the treatment of lymphoproliferative disorders and cancer. Traditional Chinese Herbal Medicine (TCHM) is widely used alone or in combination with chemotherapy to treat cancer, due to its ability to deliver a broad variety of bioactive secondary metabolites as promising sources of novel organic natural agents. In the present study, 29 varieties of medicinal plants were screened for the presence of ADA inhibitors. Extracts from Reynoutria japonica, Glycyrrhiza uralensis, Lithospermum erythrorhizon, Magnolia officinalis, Gardenia jasminoides, Stephania tetrandra, Commiphora myrrha, Raphanus sativus and Corydalis yanhusuo demonstrated strong ADA inhibition with rates greater than 50%. However, Reynoutria japonica possessed the highest ADA inhibitory activity at 95.26% and so was used in our study for isolating the ADA inhibitor to be further studied. Eight compounds were obtained and their structures were identified. The compound H1 had strong ADA inhibitory activity and was deduced to be emodin by 1H and 13C-NMR spectroscopic analysis with an IC50 of 0.629 mM. The molecular docking data showed that emodin could bind tightly to the active site of ADA. Our results demonstrated that emodin displayed a new biological activity which is ADA inhibitory activity with high cytotoxic activity against K562 leukemia cells. The bioactivity of cordycepin was significantly increased when used in combination with emodin. Emodin may represent a good candidate anti-cancer therapy and adenosine protective agent.

Clofarabine: a next-generation deoxyadenosine analogue

Acute lymphoblastic leukaemia (ALL) is the most common of the paediatric leukaemias. It is estimated that the use of modern combination chemotherapy results in long-term remission in nearly 80% of children diagnosed with ALL. Despite therapy advances, approximately 20% of children with ALL, experience leukaemia relapse. Clofarabine (2-chloro-2’-fluoro-2’-deoxy-9-β-D-arabinofuranosyladenine) is a second-generation nucleoside analogue and is structurally related to fludarabine and cladribine which are widely used in the treatment of lymphoproliferative disorders. Clofarabine exhibits greater affinity to deoxycytidine kinase (dCyd kinase) and prolonged retention in leukaemic blasts compared to fludarabine and cladribine. Clofarabine inhibits both DNA polymerases and ribonucleotide reductase (RNR). This results in impaired DNA synthesis through inhibition of DNA elongation as well as depletion of deoxyribonucleotides. Accumulation of clofarabine triphosphate, in the blasts of patients with refractory leukemia has been demonstrated. Prolonged intracellular half-life of 24 hours for clofarabine triphosphate. Clofarabine is indicated for the treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia after at least two prior regimens.

Glutaminase free l-asparaginase from Vibrio cholerae: Heterologous expression, purification and biochemical characterization

l-asparaginase is used as a pivotal agent in treatment of lympho proliferative disorders and holds an excessive demand for food processing aids. Most of the l-asparaginases possess glutaminase activity which might lead to side effects during the treatment. The search for new therapeutic enzymes is of great interest in both medical and food applications. In this study, Vibrio cholerael-asparaginase was recombinantly overexpressed in E. coli, purified to homogeneity and molecular size was estimated to be 36.6kDa. Recombinant enzyme showed an optimum pH and temperature of 7.0 and 37°C respectively. The Km and Vmax of the enzyme for l-asparagine was 1.1mM and 1006μM/min respectively. The enzyme is highly specific for l-asparagine and did not show glutaminase activity. The enzyme possessed high half life time and good stability over a wide range of physiological conditions. Tm of the enzyme was found to be 81°C by circular dichroism and differential scanning calorimetric techniques. This enzyme possesses novel properties such as (i) glutaminase free l-asparaginase activity, (ii) very high Vmax value with high affinity and (iii) high stability at 30°C (half-life time of 2.9days).

Ibrutinib, a BTK inhibitor used for treatment of lymphoproliferative disorders, eliminates both aeroallergen skin test and basophil activation test reactivity in allergic cancer patients receiving drug

Ibrutinib, a BTK inhibitor used for treatment of lymphoproliferative disorders, eliminates both aeroallergen skin test and basophil activation test reactivity in allergic cancer patients receiving drug

Accurate Real-Time Diagnosis of Lymphoproliferative Disorders in Malawi Through Clinicopathologic Teleconferences: A Model for Pathology Services in Sub-Saharan Africa.

The incidence of lymphoproliferative disorders (LPDs) is increasing in sub-Saharan Africa (SSA) due to population growth, aging, and human immunodeficiency virus (HIV). Despite significant burden, resources for diagnosis and treatment of LPDs are limited, with little infrastructure to deliver modern pathology services. Diagnostic and therapeutic decisions are therefore frequently made without tissue confirmation, leading to high rates of misdiagnosis and inappropriate treatment. We have established a laboratory in Malawi to support clinical and research efforts at a national teaching hospital. Consensus real-time diagnoses are rendered by local pathologists after weekly clinicopathologic teleconferences involving clinicians and pathologists from the United States and Malawi. Additional ancillary studies are then performed in the United States prior to final diagnosis. We report our first 2 years' experience and demonstrate high concordance between real-time diagnoses in Malawi and final diagnoses in the United States (5% major discordance rate for formalin-fixed, paraffin-embedded samples). In addition, we describe characteristics of pathologically confirmed LPDs in Malawi, highlighting differences by HIV status. Our multidisciplinary approach can be a model for strong pathology services that provide direct, real-time support to clinical care and research in SSA.

Role of the functional MNS16A VNTR-243 variant of the human telomerase reverse transcriptase gene in progression and response to therapy of patients with non-Hodgkin's B-cell lymphomas.

MNS16A is a functional polymorphic tandem repeat within the human telomerase reverse transcriptase (hTERT) gene. To investigate whether any of the MNS16A repeats represents a genetic risk factor for NHL susceptibility, progression of or response to therapy in 75 patients with non-Hodgkin's lymphomas (NHLs) and 126 healthy individuals were genotyped using the PCR-VNTR technique. A slightly higher frequency of the MNS16A VNTR-243 variant was detected among patients who did not respond to treatment (NR) as compared to patients with complete or partial remission (0.83 vs. 0.51, P = 0.055). NR patients more frequently developed aggressive than indolent type of the disease (0.92 vs. 0.41, P = 0.001). The VNTR-243 allele was more frequently detected among patients with an intermediate-high/high International Prognostic Index (IPI 3-4) score (P = 0.063), especially in patients with advanced age and IPI 3-4 (P = 0.040). In multivariate analysis, higher IPI 3-4 score (OR = 11.364, P = 0.051) and aggressive type of the disease (OR = 18.182, P = 0.012) were found to be independent genetic markers associated with nonresponse to treatment. Presence of the MNS16A VNTR-243 variant also strongly tended to affect the risk of a less favourable response to therapy and was more frequently present among nonresponders (OR = 5.848, P = 0.059). Genetic variation within the hTERT gene may affect the progression and treatment of lymphoproliferative disorders.

A novel recurrent NPM1-TYK2 gene fusion in cutaneous CD30-positive lymphoproliferative disorders

AbstractThe spectrum of cutaneous CD30-positive lymphoproliferative disorders (LPDs) includes lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma. Chromosomal translocations targeting tyrosine kinases in CD30-positive LPDs have not been described. Using whole-transcriptome sequencing, we identified a chimeric fusion involving NPM1 (5q35) and TYK2 (19p13) that encodes an NPM1-TYK2 protein containing the oligomerization domain of NPM1 and an intact catalytic domain in TYK2. Fluorescence in situ hybridization revealed NPM1-TYK2 fusions in 2 of 47 (4%) primary cases of CD30-positive LPDs and was absent in other mature T-cell neoplasms (n = 151). Functionally, NPM1-TYK2 induced constitutive TYK2, signal transducer and activator of transcription 1 (STAT1), STAT3, and STAT5 activation. Conversely, a kinase-defective NPM1-TYK2 mutant abrogated STAT1/3/5 signaling. Finally, short hairpin RNA–mediated silencing of TYK2 abrogated lymphoma cell growth. This is the first report of recurrent translocations involving TYK2, and it highlights the novel therapeutic opportunities in the treatment of CD30-positive LPDs with TYK2 translocations.

Allogeneic Stem Cell Transplantation with Immunodepleted Grafts for Lymphoproliferative Malignancies

Introduction: The treatment of lymphoproliferative disorders that fail initial therapy remains unsatisfactory. Allogeneic stem cell transplantation can be curative but has been associated with high treatment related mortality, particularly from graft vs. host disease (GvHD). Immunodepletion of the peripheral blood stem cell (PBSC) graft with alemtuzumab effectively prevents GvHD.Methods: Patients with lymphoma (excluding diffuse large B-cell) in second or subsequent response were offered allogeneic stem cell transplantation if they had a human leukocyte antigen (HLA) compatible donor. Haematopoietic stem cells were mobilized with filgrastim (5-10 ug/kg) and PBSC were collected by apheresis. Patients were conditioned with myeloablative doses of chemotherapy or radiotherapy. For GvHD prophylaxis mobilized donor blood stem cells were incubated ex vivo with alemtuzumab (in the bag) for 30 minutes and infused intravenously. Post transplantation patients received therapeutic blood levels of cyclosporine until day 90. The end points of the study were frequency of GvHD, transplant mortality, disease recurrence and overall survival (OS) rates.Results: Sixty one consecutive patients with lymphoma (follicular 17, marginal zone 2, Waldestrom’s macroglobulinaemia 2, transformed 16, peripheral T-cell 16 [all ALK negative] and lymphoblastic 8) underwent allogeneic transplantation. None had received a previous transplant. PBPC were from siblings in 53 patients and 8 from unrelated donors. Twenty patients were female and the median age was 47 years. The median CD34+ cell number infused was 4.71 (1.31 – 17.88) x10^6/kg. The median dose of alemtuzumab added into the bag was 10 mg. All recovered the blood counts at median of 13 days. Seventeen (28%) patients died, 11 (18%) of transplant related causes. Chimerism studies performed in 42 patients showed full donor chimerism in each case. GvHD (> grade 1) was seen in 8 patients (13%). Cytomegalovirus reactivation occurred in 21% but all responded to gancyclovir. Seventeen patients died, 11 (18%) of treatment related complications. Eight patients had disease recurrence, two of three achieved further response after donor leukocyte infusion and six died of the malignancy. At median follow up of 2260 15-4412) days 71% are alive in response. There was no difference in survival among the 4 histological groups or between chemotherapy and radiotherapy based conditioning. In univariate analysis female donor gender (for male patients) and GvHD were significant adverse factors for survival. Cox analysis showed that occurrence of GvHD (p= 0.001) was an independent significantly adverse factor for survival.Conclusions: We conclude that ex vivo immunodepletion of grafts with alemtuzumab leads to reduced rates of GvHD and results in lesser treatment related mortality despite myeloablative conditioning. Recurrence rates appear low suggesting that in the absence of GvHD prescribing dose intense conditioning and allogeneic stem cell transplantation earlier, before the malignancy is refractory, could be an effective strategy for patients with advanced lymphoma. DisclosuresNo relevant conflicts of interest to declare.

Non-pegylated liposomal doxorubicin in lymphoma: patterns of toxicity and outcome in a large observational trial.

The anthracycline doxorubicin plays a major role in the treatment of lymphoproliferative disorders. However, its use is often limited due to cardiac toxicity, which seems to be much less in the liposomal non-pegylated formulation (Myocet®). The aim of this study was the evaluation of efficacy and toxicity of Myocet®-containing treatment regimens, with a focus on cardiotoxicity during treatment in lymphoma patients. A total of 326 consecutive patients, treated between March 2008 and December 2013 in 11 Austrian and 1 Italian cancer centers, were retrospectively assessed. Patients' baseline and treatment-related parameters were obtained by reviewing hospital records. Median age was 74 years (range 26-93). The most common histology was DLBCL (60 %), followed by FL (13 %) and MCL (8 %). At least one cardiovascular comorbidity was present in 72 % of patients. Most common grade 3/4 toxicities were hematologic, namely, leukopenia, neutropenia, thrombocytopenia, and febrile neutropenia in 44, 40, 17, and 16 %. Overall, 43 patients suffered a cardiac event (any grade) with most patients developing congestive heart failure. Parameters significantly associated with severe cardiac events (grades 3-5) were the presence of cardiovascular comorbidities, chronic obstructive pulmonary disease, and elevated baseline NT-proBNP. Treatment response after first line Myocet®-containing therapy was ≥58 % among all entities (range 58-86 %) and therefore comparable to those of conventional therapeutic regimens. Herein, we provide a detailed toxicity profile of Myocet®-containing chemotherapy regimens. Despite the high rate of patients with preexisting comorbidities, the number of adverse events was encouraging. However, these results need to be confirmed in a prospective randomized trial.

Clinical features and outcomes of 9 patients with immunodeficiency-associated lymphoproliferative disorders treated at a single institution.

Immunodeficiency-associated lymphoproliferative disorders (LPD) represent a rare life-threatening clinical entity characterized by heterogeneous histological findings that range from polymorphic to monomorphic proliferated abnormal lymphocytes. Currently, there is no standard treatment for LPD. To elucidate the clinical features and treatment outcomes of immunodeficiency-associated LPD patients with rheumatoid arthritis (RA), we retrospectively evaluated 9 cases observed over a 5-year period. The diagnoses of these patients included 5 diffuse large B-cell lymphomas, 3 LPD, and 1 mucosa-associated lymphoid tissue lymphoma. At initial diagnosis, 6 patients had advanced-stage RA, and half of these underwent total knee arthroplasty. All patients with RA received methotrexate (MTX) and low-dose prednisolone. Biologics were administered to 4 of 9 patients. After the development of immunodeficiency-associated LPD, MTX discontinuation resulted in 5 complete remissions (CR), 1 partial remission, and 3 cases of stable disease. Relapse was observed in 3 of 5 CR patients in the MTX-withdrawal remission group. Subsequently, conventional chemotherapy, rituximab, and radiation were administered to 4, 3, and 1 patient, respectively. These treatments induced a second CR. In the chemotherapy group, 1 patient developed acute myocardial infarction and another experienced ileus and pulmonary abscess. In the rituximab group, no severe complications were observed. Consequently, all patients remained disease-free during the median 23-month follow-up period. Our results indicate that, depending on the RA disease stage, performance status, and extent of treatment response, less intensive treatments than those commonly indicated for non-Hodgkin lymphoma, involving MTX discontinuation and subsequent therapy containing rituximab, might be an efficient therapeutic strategy for immunodeficiency-associated LPD.

Autophagy as a pathogenic mechanism and drug target in lymphoproliferative disorders

Autophagy represents a key mechanism of cytoprotection that can be activated by a variety of extracellular and intracellular stresses and allows the cell to sequester cytoplasmic components and damaged organelles, delivering them to lysosomes for degradation and recycling. However, the autophagy process has also been associated with the death of the cell. It has been demonstrated to be constitutive in some instances and inducible in others, and the idea that it could represent a pathogenetic determinant as well as a possible prognostic tool and a therapeutic target in a plethora of human diseases has recently been considered. Among these, cancer represents a major one. In this review, we recapitulate the critical implications of autophagy in the pathogenesis, progression, and treatment of lymphoproliferative disorders. Leukemias and lymphomas, in fact, represent paradigmatic human diseases in which advances have recently been made in this respect.

Biodistribution of Rhenium Cluster Complex K4[Re6S8(CN)6] in the Body of Laboratory Rats

We studied the biodistribution of luminescent octahedral rhenium cluster complex K4[Re6S8(CN)6], a promising agent for photodynamic therapy. It was shown that rhenium complex [Re6S8(CN)6](4-)is mainly accumulated in the liver, the central organ of metabolism, and can be excreted by the kidneys. The cluster complex was also accumulated in the spleen in significant amount, which makes it a promising agent for creation of preparations for diagnostics and treatment of lymphoproliferative disorders. The mean lethal dose of the cluster complex was 0.38 g/kg.

Bendamustine Associated with Irreversible Ascending Paralysis

Bendamustine is an alkylating agent currently used in the treatment of lymphoproliferative disorders. Many adverse effects, including a rare case of reversible neurotoxicity, have been reported in association with bendamustine. Herein, we report the first case of irreversible ascending paralysis related to bendamustine.

Lenalidomide in the Treatment of Lymphoproliferative Disorders and Multiple Myeloma

Lenalidomide in the Treatment of Lymphoproliferative Disorders and Multiple Myeloma

Obinutuzumab for the treatment of lymphoproliferative disorders

Introduction: Targeted therapy against CD20 with the mAb rituximab has led to significant improvements in survival for patients with B-cell non-Hodgkin's lymphoma (NHL). Despite these improvements, many patients relapse and/or become refractory after rituximab-containing therapies and thus better therapies are required for NHL.Areas covered: Obinutuzumab is a novel, humanized, anti-CD20 mAb currently being investigated in Phase III studies in comparison to rituximab. An overview of obinutuzumab, its mechanisms of action and the results of pre-clinical and Phase I/II studies are presented.Expert opinion: Pre-clinical studies suggest that obinutuzumab is a more potent anti-CD20 mAb than Rituximab at inducing antibody-dependent cellular cytotoxicity (ADCC) and direct cell death (DCD). Obinutuzumab is safe and effective in CD20 + NHL and further study is warranted. Results of ongoing Phase III clinical trials comparing Obinutuzumab to Rituximab in different disease settings and with different chemotherapy regimens are eagerly awaited.

MGUS: Proposal for outpatient management

The term monoclonal gammopathy of undetermined significance (MGUS) indicates the presence of a monoclonal protein (M-protein) without features of multiple myeloma, Waldenstrom’s macroglobulinemia, primary amyloidosis or malignant lymphoproliferative disorders (LPD). While several guidelines on the treatment of LPD exist, many doubts and perplexities still exist on who should treat a MGUS, when and how. Even where MGUS does not require any therapy, the risk of progression to a LPD is 1% per year. This risk does not diminish over time and persists even in patients (pts) whose condition has remained stable for decades, and a prolonged follow up is, therefore, recommended. We met primary care doctors to share and agree on criteria for the management of outpatients with MGUS. Our aim is to draw up guidelines or, at least, suggestions that may help to determine which MGUS pts could be cared for by the primary care doctor and which should be followed by the hematologist. We suggest that once a MGUS is diagnosed, the primary care physician will attend patients with M-protein 15 g/L, or M-protein IgA > 10 g/L, or IgM > 10 g/L, or any M-protein with end-organ damage (not attributable to any others causes) or with signs and symptoms of LPD, or rapidly increasing M-protein (>

Interleukin-15 enhances rituximab-dependent cytotoxicity against chronic lymphocytic leukemia cells and overcomes transforming growth factor beta-mediated immunosuppression

Chemoimmunotherapy with anti-CD20 monoclonal antibody rituximab is increasingly used for the treatment of patients with chronic lymphocytic leukemia (CLL). Antibody-dependent cytotoxicity (ADCC) is one of the most important mechanisms of action of rituximab against B-cell malignancies. We studied ways to increase the cytotoxic effect of rituximab on CLL cells by enhancing ADCC. Peripheral blood mononuclear cell (PBMC) or purified natural killer (NK) cells from healthy donors were activated with interleukin-15 (IL-15) and cultured with rituximab-coated CLL cells, and ADCC was evaluated using a (51)chromium release assay. The IL-15 significantly enhanced invitro ADCC against CLL cells, and this effect was mainly mediated by NK cells. The IL-15 treated effector cells with the low affinity FcγRIIIA receptor (158FF) had an ADCC comparable to those with the high affinity FcγRIIIA form (158VF). Inaddition, IL-15 enhanced rituximab-mediated ADCC of CLL cells in the presence of transforming growth factor-beta. The IL-15 increases rituximab-mediated ADCC against CLL, and supports the use of such agents with the goal of improving clinical response to chemoimmunotherapy in patients with CLL.