Kevin Tay

Janus Kinase 3–Activating Mutations Identified in Natural Killer/T-cell Lymphoma

UNLABELLED The molecular pathogenesis of natural killer/T-cell lymphoma (NKTCL) is not well understood. We conducted whole-exome sequencing and identified Janus kinase 3 (JAK3) somatic-activating mutations (A572V and A573V) in 2 of 4 patients with NKTCLs. Further validation of the prevalence of JAK3 mutations was determined by Sanger sequencing and high-resolution melt (HRM) analysis in an additional 61 cases. In total, 23 of 65 (35.4%) cases harbored JAK3 mutations. Functional characterization of the JAK3 mutations support its involvement in cytokine-independent JAK/STAT constitutive activation leading to increased cell growth. Moreover, treatment of both JAK3-mutant and wild-type NKTCL cell lines with a novel pan-JAK inhibitor, CP-690550, resulted in dose-dependent reduction of phosphorylated STAT5, reduced cell viability, and increased apoptosis. Hence, targeting the deregulated JAK/STAT pathway could be a promising therapy for patients with NKTCLs. SIGNIFICANCE Gene mutations causing NKTCL have not been fully identified. Through exome sequencing, we identified activating mutations of JAK3 that may play a significant role in the pathogenesis of NKTCLs. Our findings have important implications for the management of patients with NKTCLs.

Hepatitis B virus reactivation in B-cell lymphoma patients treated with rituximab: analysis from the Asia Lymphoma Study Group.

BACKGROUND Hepatitis B virus (HBV) reactivation is increasing, as rituximab has become widely used for B-cell lymphoma. Thus, prevention and management of HBV reactivation are important in HBV-endemic areas. METHODS Hepatitis B virus (HBV) reactivation in HBV surface antigen (HBsAg)-positive patients and HBsAg-negative/HBV core antibody (HBcAb)-positive patients who received rituximab-containing chemotherapy was investigated by the Asia Lymphoma Study Group via retrospective (n=340), and the results were compared to cross-sectional analysis with patients who were prospectively monitored in a single institute (n=127). The goal of the study was to define the frequency of HBV reactivation and the efficacy of antiviral prophylaxis. RESULTS HBV reactivation was found in 27.8% of HBsAg-positive patients (45/162) in the retrospective analysis, being significantly less frequent in patients receiving antiviral prophylaxis than those not (22.9%, 32/140 versus 59.1%, 13/22; p<0.001). Lamivudine was most commonly used (96/162, 59.3%), but more than 20% of HBsAg-positive patients showed breakthrough HBV reactivation. In the cross-sectional analysis, a reduced rate of HBV reactivation occurred for entecavir as compared with lamivudine prophylaxis (6.3% versus 39.3%; p<0.05). HBV DNA monitoring of HBsAg-negative/HBcAb-positive patients in the cross-sectional analysis showed HBV reactivation in only 2.4% of cases. CONCLUSIONS This is the largest study of HBV reactivation in patients receiving rituximab-containing chemotherapy to date, and we defined the probability of HBV reactivation in an HBV-endemic region.

JAK-STAT and G-protein-coupled receptor signaling pathways are frequently altered in epitheliotropic intestinal T-cell lymphoma

Epitheliotropic intestinal T-cell lymphoma (EITL, also known as type II enteropathy-associated T-cell lymphoma) is an aggressive intestinal disease with poor prognosis and its molecular alterations have not been comprehensively characterized. We aimed to identify actionable easy-to-screen alterations that would allow better diagnostics and/or treatment of this deadly disease. By performing whole-exome sequencing of four EITL tumor-normal pairs, followed by amplicon deep sequencing of 42 tumor samples, frequent alterations of the JAK-STAT and G-protein-coupled receptor (GPCR) signaling pathways were discovered in a large portion of samples. Specifically, STAT5B was mutated in a remarkable 63% of cases, JAK3 in 35% and GNAI2 in 24%, with the majority occurring at known activating hotspots in key functional domains. Moreover, STAT5B locus carried copy-neutral loss of heterozygosity resulting in the duplication of the mutant copy, suggesting the importance of mutant STAT5B dosage for the development of EITL. Dysregulation of the JAK-STAT and GPCR pathways was also supported by gene expression profiling and further verified in patient tumor samples. In vitro overexpression of GNAI2 mutants led to the upregulation of pERK1/2, a member of MEK-ERK pathway. Notably, inhibitors of both JAK-STAT and MEK-ERK pathways effectively reduced viability of patient-derived primary EITL cells, indicating potential therapeutic strategies for this neoplasm with no effective treatment currently available.

Panobinostat in combination with bortezomib in patients with relapsed or refractory peripheral T-cell lymphoma: an open-label, multicentre phase 2 trial

BACKGROUND Patients with relapsed or refractory peripheral T-cell lymphoma have a poor prognosis after conventional chemotherapy. Approved novel agents have only modest single-agent activity in most subtypes of peripheral T-cell lymphoma. Panobinostat is a potent oral pan-deacetylase inhibitor. Findings of many preclinical studies have shown synergistic antilymphoma activity when panobinostat is combined with the proteasome inhibitor bortezomib. We aimed to study the effect of panobinostat and bortezomib in patients with relapsed or refractory peripheral T-cell lymphoma. METHODS In this open-label, multicentre phase 2 trial, we recruited patients aged 21 years or older with relapsed or refractory peripheral T-cell lymphoma who had received at least one previous line of systemic therapy from five tertiary hospitals in Singapore, Malaysia, and South Korea. Patients received 20 mg oral panobinostat three times a week and 1·3 mg/m(2) intravenous bortezomib two times a week, both for 2 of 3 weeks for up to eight cycles. The primary endpoint was the proportion of patients who achieved an objective response in accordance with the International Working Group revised response criteria; analyses were by intention to treat. The study is completed and is registered with ClinicalTrials.gov, number NCT00901147. FINDINGS Between Nov 9, 2009, and Nov 26, 2013, we enrolled 25 patients with various histological subtypes of peripheral T-cell lymphoma. Of 23 patients assessable for responses, ten (43%, 95% CI 23-63) patients had an objective response, of which five were complete responses. Serious adverse events were reported in ten (40%) of 25 patients. Common treatment-related grade 3-4 adverse events included thrombocytopenia (17 [68%]), neutropenia (ten [40%]), diarrhoea (five [20%]), and asthenia or fatigue (two [8%]). We recorded peripheral neuropathy of any grade in ten (40%) patients. INTERPRETATION Combined proteasome and histone deacetylase inhibition is safe and feasible and shows encouraging activity for patients with peripheral T-cell lymphoma. Our findings validate those of preclinical studies showing synergism in the combination and represent a rational way forward in harnessing the full potential of novel agents in peripheral T-cell lymphoma. FUNDING Novartis Pharmaceuticals, Janssen Pharmaceuticals, and Singhealth Foundation.

Comparison of daily filgrastim and pegfilgrastim to prevent febrile neutropenia in Asian lymphoma patients.

Aim:  Febrile neutropenia (FN) is a highly prevalent complication of chemotherapy, particularly in patients with non‐Hodgkins lymphoma. This study aimed to compare the efficacy of filgrastim and pegfilgrastim in Asian lymphoma patients by evaluating the incidence of FN and associated complications.

Peripheral T-cell lymphoma: review and updates of current management strategies.

The classification of T-cell and natural-killer- (NK-) cell lymphomas has been updated in the 4th edition of the World Health Organization (WHO) classification of tumors of the haematopoietic and lymphoid tissue published in 2008. Based on recent epidemiological studies, NK-cell lymphomas occur almost exclusively in Asia and South America, although T-cell lymphomas appear to occur in the East as commonly as in the West. Due to the low prevalence of this disease, diagnosis and optimal treatment of patients have not been studied prospectively in large randomized trials. Nevertheless, there has been development in the understanding of T-cell lymphomas and how they should be managed; FDG-PET emerges as an increasingly important tool in diagnosis, gene-expression signatures may aid with prognostication in the future, and novel therapies are currently being studied to improve outcomes in T-cell lymphomas. More work, however, needs to be done, and international collaboration will be pertinent to deriving meaningful results from future clinical studies.

Management of tumor lysis syndrome with a single fixed dose of rasburicase in Asian lymphoma patients: A case series and literature review

Aim:  Recently, a number of studies have demonstrated the effectiveness of a single reduced dose of rasburicase for the management of tumor lysis syndrome (TLS) in adults. Whether Asian lymphoma patients similarly respond to a single dose of rasburicase is currently unknown. We aim to assess the efficacy of a single dose rasburicase in preventing TLS in Asian lymphoma patients.

Clinical pharmacy services and research for lymphoma patients at a cancer center

At the National Cancer Centre Singapore, which is currently the largest ambulatory cancer centre in Singapore, clinical pharmacists have taken upon responsibilities to provide direct pharmaceutical care in the center’s lymphoma team since 2006. Given the complexity and intricacies of lymphoma treatments, clinical pharmacists are often positioned to ensure supportive care is optimized among these patients. Besides management of chemotherapy-related and supportive care issues, clinical pharmacists play a pivotal role in guiding cost-effective and safe prescribing. In collaboration with the medical team, they are also involved in conducting practice research in order to optimize the delivery of pharmaceutical care. In this report, the dedicated services and research activities conducted by clinical pharmacists of a lymphoma team will be discussed.

Carotid artery inflammation associated with gemcitabine-based therapy: a special report

Vasculitis is an inflammation that can present as acute or chronic in nature, which causes changes in the walls of blood vessels, including thickening, weakening, narrowing and scarring. Gemcitabine, an antimetabolite chemotherapeutic agent, is generally well tolerated with a favorable side effect profile. However, there is increasing evidence that it is associated with vasculitis, which can affect small and large vessels. In this case report, we report a patient who has experienced fever with severe tenderness over right carotid artery, which occurred on the fifth day after the administration of gemcitabine. The exact mechanism of gemcitabine-induced vasculitis is unknown but cessation of gemcitabine and initiation of anti-inflammatory treatment appears to aid in the resolution of the clinical syndrome.