Recent updates on central nervous system prophylaxis in patients with high-risk diffuse large B-cell lymphoma.

The use of central nervous system (CNS) prophylaxis for patients with diffuse large B-cell lymphoma (DLBCL) remains controversial. Although uncommon, CNS relapses are invariably fatal in this otherwise curable disease. Accurate identification of patients at risk and the optimal approach to CNS prophylaxis therefore remains an area of unmet need. The existing literature, largely retrospective in nature, provides mixed conclusions regarding the efficacy of CNS prophylaxis. The utility of CNS prophylaxis has itself been challenged. In this review, we dissect the issues which render the value of CNS prophylaxis uncertain. We first compare international clinical guidelines for CNS prophylaxis. We then interrogate the factors that should be used to identify high-risk patients accurately. We also explore how clinical patterns of CNS relapse have changed in the pre-rituximab and rituximab era. We then discuss the efficacy of CNS-directed approaches, intensification of systemic treatment and other novel approaches in CNS prophylaxis. Improved diagnostics for early detection of CNS relapses and newer therapeutics for CNS prophylaxis are areas of active investigation. In an area where prospective, randomized studies are impracticable and lacking, guidance for the use of CNS prophylaxis will depend on rigorous statistical review of retrospective data.

A Systematic Review and Meta-Analysis of Mapping Biopsy for Primary Extramammary Paget's Disease in Reducing Recurrence Following Surgical Excision.

Objective: To examine the association between the performance of mapping biopsies and surgical outcomes postexcision of extramammary Paget's disease (EMPD). Background: Primary EMPD is a rare entity associated with poorly defined surgical margins and difficult-to-access sites of lesions. Surgical resection with clear margins remains the preferred management method. The use of mapping biopsies might be beneficial, particularly in lowering disease recurrence. Methods: Available literature was reviewed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses methodology before a fixed-effect meta-analysis was performed to identify the presence of a correlation between performing mapping biopsies and positive margins on permanent sections as well as disease-free survival. Additional study results not included in the quantitative assessment were qualitatively assessed and reported. Results: A total of 12 studies were shortlisted for final analysis. 294 patients who underwent mapping biopsies and 48 patients who did not undergo mapping biopsies were included in the assessment. Forest plot analysis revealed a pooled rate ratio of 0.50 (95% CI, 0.32-0.77) in the prevalence of positive margins in patients with mapping biopsies performed as compared to patients without. The pooled rate ratio of the prevalence of disease-free survival in patients with mapping biopsies performed as compared to patients without was 1.38 (95% CI, 1.03-1.84). Qualitative assessment of the remaining selected studies revealed equivocal results. Conclusions: Mapping biopsies are able to improve EMPD surgical excision outcomes but given the rarity of the disease and heterogeneity of mapping biopsy procedures, further confirmation with randomized controlled trials or a larger patient pool is necessary.

Multi-omic profiling and real time ex vivo modelling of imatinib-resistant dermatofibrosarcoma protuberans with fibrosarcomatous transformation.

Dermatofibrosarcoma protuberans (DFSP) is a rare and indolent cutaneous sarcoma, with the risk of aggressive fibro-sarcomatous transformation. Limited effective options are available for un-resectable or metastatic DFSP beyond targeting the oncogenic PDGF pathway with imatinib therapy. We established a patient-derived xenograft (PDX) and cell line model (designated MDFSP-S1) of imatinib-resistant DFSP with fibro-sarcomatous transformation. Whole genome sequencing identified high-level amplification at chromosomes 17 and 22, whilst homozygous deep deletion was demonstrated at chromosome 9 (CDKN2A, CDKN2B, MTAP). RNA sequencing followed by Sanger sequencing confirmed the pathognomonic COL1A1-PDGFB t (17;22) rearrangement in the original tumour, PDX and cell line model. Immunohistochemistry profiles of the PDX model were consistent with the patient's tumour sample (CD34 + /MIB1 + /SOX10- ). Gene set enrichment analysis highlighted top-scoring Hallmark gene sets in several oncogenic signalling pathways, including potentially targetable MTORC1 signalling and angiogenesis pathways. Antiangiogenic agents (sunitinib, regorafenib, pazopanib, axitinib) and the third-generation irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor osimertinib exhibited modest anti-proliferative activity in the cell line, with IC50 values between 1 and 10 µM at 72 h. No significant activity was observed with imatinib, palbociclib, everolimus, olaparib, gefitinib and erlotinib (IC50 all > 10 µM). In conclusion, we established MDFSP-S1, a new PDX and cell line model of imatinib-resistant DFSP with fibro-sarcomatous transformation.

Clinical features and prognostic outcomes of angioimmunoblastic T cell lymphoma in an Asian multicenter study.

In our Asian multicenter retrospective study, we investigated the clinical prognostic factors affecting the outcomes of AITL patients and identified a novel prognostic index relevant in the Asian context. In our 174-patient cohort, the median PFS and OS was 1.8 years and 5.6 years respectively. Age > 60, bone marrow involvement, total white cell count >12 × 109/L and raised serum lactate dehydrogenase were associated with poorer PFS and OS in multivariate analyses. This allowed for a prognostic index (AITL-PI) differentiating patients into low (0-1 factors, n = 64), moderate (2 factors, n = 59) and high-risk (3-4 factors, n = 49) subgroups with 5-year OS of 84.0%, 44.0% and 28.0% respectively (p < 0.0001). POD24 proved to be strongly prognostic (5-year OS 24% vs 89%, p < 0.0001). Exploratory gene expression studies were performed and disparate immune cell profiles and cell signaling signatures were seen in the low risk group as compared to the intermediate and high risk groups.

Longitudinal study evaluating post-ICU syndrome differences between acute care surgery and trauma SICU survivors.

BACKGROUND: Post-intensive care unit (ICU) syndrome (PICS) occurs at an exorbitant rate in surgical ICU (SICU) survivors. It remains unknown if critical illness due to trauma versus acute care surgery (ACS) may represent different pathophysiologic entities. In this longitudinal study, we determined if admission criteria in a cohort of trauma and ACS patients were associated with differences in the occurrence of PICS. METHODS: Patients were 18 years or older, admitted to a Level I trauma center to the trauma or ACS services, remained in the SICU for ≥72 hours, and were seen in an ICU Recovery Center at 2 weeks, 12 weeks, and 24 weeks after hospital discharge. Post-ICU syndrome sequelae were diagnosed by dedicated specialist staffing using clinical criteria and screening questionnaires. The PICS symptoms were distilled into physical, cognitive, and psychiatric categories. Preadmission histories, hospital courses, and recovery data were collected via retrospective chart review. RESULTS: One hundred twenty-six patients were included: 74 (57.3%) trauma patients and 55 (42.6%) ACS patients. Prehospital psychosocial histories were similar between groups. Acute care surgery patients had a significantly longer hospital course, higher APACHE II and III scores, were intubated for longer, and had higher rates of sepsis, acute renal failure, open abdomen, and hospital readmissions. At the 2-week follow-up visit, ACS patients had higher rates of PICS sequelae (ACS, 97.8% vs. trauma 85.3%; p = 0.03), particularly in the physical (ACS, 95.6% vs. trauma 82.0%, p = 0.04), and psychiatric domains (ACS, 55.6% vs. trauma 35.0%, p = 0.04). At the 12-week and 24-week visits, rates of PICS symptoms were comparable between groups. CONCLUSION: The occurrence of PICS is extraordinarily high in both trauma and ACS SICU survivors. Despite entering the SICU with similar psychosocial histories, the two cohorts have different pathophysiologic experiences, which are associated with a higher rate of impairment in the ACS patients during early follow-up. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level III.

Post-Treatment Neutrophil and Lymphocyte Counts Predict Progression-Free Survival Following First-Line Chemotherapy in Hodgkin's Lymphoma.

Hodgkin's lymphoma carries an excellent prognosis with modern chemotherapy, but a significant proportion of patients remain refractory to or relapse after first-line treatment. Immunological changes post-treatment, such as chemotherapy-induced neutropenia (CIN) or lymphopenia, have shown prognostic significance in multiple tumor types. Our study aims to investigate the prognostic value of immunologic changes in Hodgkin's lymphoma by examining the post-treatment lymphocyte count (pALC), neutrophil count (pANC) and the neutrophil-lymphocyte ratio (pNLR). Patients treated for classical Hodgkin's lymphoma at the National Cancer Centre Singapore using ABVD-based regimens were retrospectively analyzed. An optimal cut-off value for high pANC, low pALC and high pNLR in predicting progression-free survival was determined by receiver operating curve analysis. Survival analysis was performed using the Kaplan-Meier method and multivariable Cox proportional models. Overall OS and PFS were excellent, with a 5-year OS of 99.2% and a 5-year PFS of 88.2%. Poorer PFS was associated with high pANC (HR 2.99, p = 0.0392), low pALC (HR 3.95, p = 0.0038) and high pNLR (p = 0.0078). In conclusion, high pANC, low pALC and high pNLR confer a poorer prognosis for Hodgkin's lymphoma. Future studies should evaluate the potential of improving treatment outcomes by the adjustment of chemotherapy dose intensity based on post-treatment blood counts.

Burkitt lymphoma - no impact of HIV status on outcomes with rituximab-based chemoimmunotherapy.

We analyzed the prognostic factors for treatment outcomes amongst 34 patients with adult Burkitt lymphoma (BL) who received rituximab with standard first-line chemotherapy. Seven patients had human immunodeficiency virus (HIV)-associated BL. Overall, we observed a complete remission (CR) rate of 91.2%, and 10-year progression-free survival (PFS) and overall survival (OS) was 84.8 and 88.2%, respectively. In patients with concomitant HIV, the prognosis was not different with 10-year PFS of 100% and OS of 88.2%. The majority (71.4%) of HIV-associated BL patients received dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) and had excellent outcomes with 100% CR and no relapses. Central nervous system (CNS) disease, bone marrow involvement and elevated serum lactate dehydrogenase (LDH) levels more than 3 times upper limit of normal (ULN) were associated with poorer survival outcomes. Patients with refractory disease, whilst uncommon (n = 4), had dismal outcomes. Patients with adult BL, including HIV-related cases, harbor generally good prognosis in the modern era.

Work Outcomes and Medical Costs Among Singaporean Adolescent and Young Adult Cancer Survivors.

Purpose: To quantify and evaluate trends of work outcomes and medical costs among Singaporean adolescent and young adult (AYA) cancer survivors. Methods: This cross-sectional study was conducted at the National Cancer Centre Singapore between July 2016 and October 2018. Cancer patients who were diagnosed between the age of 15 and 39 years and had completed treatment were eligible. Siblings of cancer patients were recruited as controls. Work outcomes were collected using an investigator-designed questionnaire, while cost data were extracted from the hospital database. Descriptive statistics were used to quantify work and cost outcomes. Mixed-effects logistic regression was used to compare employment rates between survivors and controls. Generalized linear models were used to characterize trends between medical costs and symptom burden. Results: A total of 29 cancer survivors and 23 sibling controls were analyzed. Approximately 80% of survivors and controls were employed at the time of survey; however, more than half of the employed survivors reported impaired work outcomes due to effects from cancer and cancer treatment, including work reallocation, absenteeism, and decreased work ability. Median productivity loss due to absenteeism in the past 3 months was estimated to be U.S. dollar (USD) 110. Total medical cost incurred within the first year after treatment completion remained high at a median of USD6592, with out-of-pocket expenditure between 17.2% and 100.0%. Conclusion: Despite their young age and having completed cancer treatment, Singaporean AYA cancer survivors may continue to experience poor work outcomes even after resuming work. High medical costs may also persist.

Treatment outcomes of T and natural-killer/T-cell lymphoma with ifosfamide, carboplatin and etoposide chemotherapy.

BACKGROUND: Contemporary data of peripheral T-cell lymphoma (PTCL) and natural-killer/T-cell lymphoma (NKTL) patients treated with ifosfamide, carboplatin and etoposide (ICE) are limited. AIMS: We performed a retrospective analysis to estimate outcomes of ICE-treated PTCL and NKTL patients at three tertiary cancer centres in Singapore. METHODS AND RESULTS: Patients were identified through lymphoma databases from National Cancer Centre Singapore (NCCS), National University Hospital, Singapore (NUHS), and Singapore General Hospital (SGH). Responses and survival outcomes were determined from electronic medical records. A total of 75 patients with a median age of 50 were included. ICE was used as first-line treatment in 14 patients (19%) and as subsequent lines of treatment in 61 patients (81%). The overall response rates (ORR) for all patients was 63% (40% complete response [CR]). The ORR and CR in the first line were 86% and 64% respectively. At a median follow-up duration of 71.0 months, the median progression-free (PFS) and overall survival (OS) for all patients were 4.4 months (95%CI, 2.7-6.0) and 16 months (95%CI, 8.3-45.4) respectively. CONCLUSION: In summary, ICE showed high ORR but poor PFS in relapsed/refractory PTCL and NKTL. ORR of ICE in the first line setting appears better than real-world CHOP data and warrants further study.

Long-term care for people treated for cancer during childhood and adolescence.

Worldwide advances in treatment and supportive care for children and adolescents with cancer have resulted in a increasing population of survivors growing into adulthood. Yet, this population is at very high risk of late occurring health problems, including significant morbidity and early mortality. Unique barriers to high-quality care for this group include knowledge gaps among both providers and survivors as well as fragmented health-care delivery during the transition from paediatric to adult care settings. Survivors of childhood and adolescent cancer are at risk for a range of late-occuring side-effects from treatment, including cardiac, endocrine, pulmonary, fertility, renal, psychological, cognitive, and socio-developmental impairments. Care coordination and transition to adult care are substantial challenges, but can be empowering for survivors and improve outcomes, and could be facilitated by clear, effective communication and support for self-management. Resources for adult clinical care teams and primary care providers include late-effects surveillance guidelines and web-based support services.

A Prognostic Model Using Post-Steroid Neutrophil-Lymphocyte Ratio Predicts Overall Survival in Primary Central Nervous System Lymphoma.

Background: Ratios of differential blood counts (hematological indices, HIs) had been identified as prognostic variables in various cancers. In primary central nervous system lymphomas (PCNSLs), higher baseline neutrophil-lymphocyte ratio (NLR) in particular was found to portend a worse overall survival. However, it was often observed that differential counts shift drastically following steroid administration. Moreover, steroids are an important part of the arsenal against PCNSL due to its potent lymphotoxic effects. We showed that the effect of steroids on differential blood cell counts and HIs could be an early biomarker for subsequent progression-free (PFS) and overall survival (OS). Methods: This study retrospectively identified all adult patients who received a brain biopsy from 2008 to 2019 and had histologically confirmed PCNSL, and included only those who received chemoimmunotherapy, with documented use of corticosteroids prior to treatment induction. Different blood cell counts and HIs were calculated at three time-points: baseline (pre steroid), pre chemoimmunotherapy (post steroid) and post chemoimmunotherapy. Tumor progression and survival data were collected and analyzed through Kaplan−Meier estimates and Cox regression. We then utilized selected variables found to be significant on Kaplan−Meier analysis to generate a decision-tree prognostic model, the NNI-NCCS score. Results: A total of 75 patients who received chemoimmunotherapy were included in the final analysis. For NLR, OS was longer with higher pre-chemoimmunotherapy (post-steroid) NLR (dichotomized at NLR ≥ 4.0, HR 0.42, 95% CI: 0.21−0.83, p = 0.01) only. For platelet-lymphocyte ratio (PLR) and lymphocyte-monocyte ratio (LMR), OS was better for lower post-chemoimmunotherapy PLR (dichotomized at PLR ≥ 241, HR 2.27, 95% CI: 1.00 to 5.18, p = 0.05) and lower pre-chemoimmunotherapy (post-steroid) LMR (dichotomized at LMR ≥25.7, HR 2.17, 95% CI: 1.10 to 4.31, p = 0.03), respectively, only. The decision-tree model using age ≤70, post-steroid NLR >4.0, and pre-steroid (baseline) NLR <2.5 and the division of patients into three risk profiles­low, medium, and high­achieved good accuracy (area-under-curve of 0.78), with good calibration (Brier score: 0.16) for predicting 2-year overall survival. Conclusion: We found that post-steroid NLR, when considered together with baseline NLR, has prognostic value, and incorporation into a prognostic model allowed for accurate and well-calibrated stratification into three risk groups.

Prognostication of diffuse large B-cell lymphoma patients with Deauville score of 3 or 4 at end-of-treatment PET evaluation: a comparison of the Deauville 5-point scale and the ΔSUVmax method.

Diffuse large B-cell lymphoma is treated with anti-CD 20 and multi-drug chemotherapy for cure. Positron emission tomography (PET) scans are performed at end of treatment (EOT) to assess response. EOT Deauville scores (DS) are equivocal for treatment response in some situations, requiring physicians to determine the need for further investigations or treatment. Studies have suggested the delta maximum standardised uptake value (ΔSUVmax) to be superior to DS for assessment of metabolic response at interim PET, although its use at EOT PET, especially in cases of equivocal response, has yet to be established. We investigated whether ΔSUVmax could better discriminate prognosis than DS 3 or 4 at EOT. ΔSUVmax did not outperform DS. Combination of DS 3 and International Prognostic Index (IPI) <3 selects for patients with extremely low risk of disease progression (HR 0.06, 95% CI 0.01 to 0.62, p 0.018) compared to DS 4 and IPI ≥3.

Treatment Outcomes and Survival Patterns of Asian Patients With Relapsed/Refractory Mantle Cell Lymphoma.

Background: Mantle cell lymphoma (MCL) is widely considered an incurable malignancy even with current therapies and relapsed/refractory (R/R) disease to primary treatment remains common. With improved treatment guidelines and the advent of novel agents, patients are increasingly being treated with more lines of regimens. However, outcomes after each line of treatment remain poorly characterized, especially in the Asian population. In this paper, we described the survival outcomes in a group of R/R MCL patients. Methods: We retrospectively studied 35 patients with R/R MCL between 1998 and 2020 at the National Cancer Centre Singapore. Patients were followed longitudinally throughout their disease course. Overall survival (OS) and progression-free survival (PFS) were determined by the Kaplan-Meier method. Results: The median OS and PFS from diagnosis were 105 and 40 months, respectively. After first relapse, the median OS and PFS were 52 and 19 months, post-second relapse 32 and 8 months, and post-third relapse 12 and 6 months, respectively. Patients older than 65 years at first relapse had shorter survival (median OS: 22 vs. 55 months, P = 0.0417; median PFS: 9 vs. 29 months, P = 0.001). Early treatment failure after first line therapy was also associated with worse survival outcomes (median OS: 13 vs. 55 months, P < 0.001; median PFS: 9 vs. 26 months, P < 0.001). Conclusion: With each relapse, survival outcomes for patients with MCL are worse. Novel treatment and contemporary outcomes of R/R MCL are encouraging and support the need for continued research in this area.

High occurrence of postintensive care syndrome identified in surgical ICU survivors after implementation of a multidisciplinary clinic.

BACKGROUND: Postintensive care syndrome (PICS) has been identified in a large proportion of medical intensive care unit survivors; however, the occurrence surgical intensive care unit (SICU) survivors is unknown. We implemented a multidisciplinary critical care outpatient clinic (CCOC) to identify the occurrence of PICS in SICU survivors. METHODS: Seventy acute care surgery and trauma patients, 18 years or older, who remained in the SICU for 72 hours or longer at a Level I trauma center were seen in CCOC at 2 weeks, 12 weeks, and 24 weeks after hospital discharge. The CCOC staffing included a nurse coordinator, social worker, critical care pharmacist, physical therapist, and acute care surgeon who identified PICS sequelae in their respective specialties by clinical criteria and screening questionnaires. RESULTS: Of 82 eligible patients, 70 (85.4%) were seen at least once for 116 total visits. Forty-three (61.4%) patients suffered traumatic injuries and 27 (38.6%) underwent emergent general surgery. Sixty-seven (95.7%) demonstrated at least one PICS criterion. Over all visits, 26 (37.1%) patients presented with one PICS criterion, 24 (34.3%) patients with two, and 17 (24.3%) with three. Cognitive impairment was observed in 29 (41.4%) patients, psychiatric in 30 (42.9%), and physical symptoms in 65 (92.9%). Activity Measure for Post-Acute Care scores improved from severe impairment at admission to full function by 12 weeks postdischarge, yet 6 Minute Walk Test scores remained below age-matched references through all visits. Patients expressed mild to moderate depression based on Patient Health Questionnaire-9 scores. A medication reconciliation was completed at 96.5% (112/116) of the visits with 116 total medication recommendations. By 24 weeks following discharge, only 26.4% (14/53) of previously employed patients had resumed work. CONCLUSION: Through the successful implementation of a multidisciplinary CCOC, this study identifies an exorbitant rate of PICS among SICU survivors. LEVEL OF EVIDENCE: Therapeutic/epidemiological, level III.

Treatment patterns and outcomes of older patients with mantle cell lymphoma in an Asian population.

BACKGROUND: Significant progress has been made in the treatment outcomes of mantle cell lymphoma (MCL) since the introduction of cytarabine and rituximab in modern regimens. However, older patients may not readily tolerate these agents nor derive benefit. We investigated the impact of age on treatment patterns and clinical outcomes of MCL patients in an Asian population. METHODS: A retrospective study was conducted on patients (n = 66) diagnosed with MCL at the National Cancer Centre Singapore between 1998 and 2018. The median follow-up duration was 40 months. Survival analyses were performed using the Kaplan-Meier method and multivariate Cox proportional models. RESULTS: The median age of the cohort was 59 years (range, 26-84), with a male predominance (73%). The majority (86%) had advanced stage 3-4 disease at diagnosis. Compared with younger patients, older patients aged ≥60 years (n = 32; 48.5%) presented more frequently with B-symptoms (75% vs 38%, p = 0.0028), anaemia (75% vs 35%, p = 0.0013), and carried higher prognostic risk scores (sMIPI high risk 84% vs 56%, p = 0.016). Non-cytarabine-based induction chemotherapy was more commonly administered in older patients (76% vs 32%, p = 0.0012). The 5-year overall survival (OS) and progression-free survival (PFS) was 68 and 25% respectively. In a multivariable model, older age (HR 3.42, 95%CI 1.48-7.92, p = 0.004) and anemia (HR 2.56, 95%CI 1.10-5.96, p = 0.029) were independently associated with poorer OS while older age (HR 2.24, 95%CI 1.21-4.14, p = 0.010) and hypoalbuminemia (HR 2.20, 95%CI 1.17-4.13, p = 0.014) were independently associated with poorer PFS. In an exploratory analysis, maintenance rituximab following induction chemotherapy improved PFS in younger patients, with median PFS of 131 months and 45 months with or without maintenance therapy respectively (HR 0.39, 95%CI 0.16-0.93, p = 0.035). In contrast, no survival benefit was observed in older patients. CONCLUSIONS: We demonstrated in our analysis that older patients with MCL may harbor adverse clinical features and may not derive benefit from maintenance rituximab, highlighting the need for further research in this area of need.

Clinical and economic evaluation of a surveillance protocol to manage hepatitis B virus (HBV) reactivation among lymphoma patients with resolved HBV infection receiving rituximab.

STUDY OBJECTIVE: To evaluate a surveillance protocol in managing the risk of hepatitis B virus (HBV) reactivation among lymphoma patients with resolved HBV infection receiving rituximab. DESIGN: Prospective, single-arm study. SETTING: National Cancer Centre, Singapore. PATIENTS: Lymphoma patients with resolved HBV infection and scheduled to receive rituximab-based treatment. INTERVENTION: Close monitoring of HBV DNA levels, ie. every 4-6 weeks during rituximab treatment, every 6-8 weeks in the first year post-treatment, and every 3-4 months in the second year post-treatment. MEASUREMENTS: The efficacy of the surveillance protocol was examined by evaluating the rates of reactivation-related events. Feasibility was evaluated based on patient adherence. An economic analysis using a cost-minimization approach was conducted to compare the costs between the surveillance protocol and universal prophylaxis with entecavir 0.5 mg daily up to 1 year after cessation of rituximab. MAIN RESULTS: A total of 66 patients provided analyzable data with a follow-up period of 966.6 months. No hepatitis flare or reactivation-related events were detected. The median adherence rate to the surveillance protocol was 90.5%. Cost savings of US$946.40 per patient over the entire surveillance period were achieved if the surveillance protocol was adopted and was most affected by changes in prophylaxis duration and the cost of antiviral prophylaxis. CONCLUSIONS: The surveillance protocol is an effective, feasible and cost-saving strategy to manage HBV reactivation among lymphoma patients with resolved HBV infection receiving rituximab.

Phase I study of selinexor in combination with dexamethasone, ifosfamide, carboplatin, etoposide chemotherapy in patients with relapsed or refractory peripheral T-cell or natural-killer/T-cell lymphoma

Selinexor is a selective inhibitor of nuclear export with anti-cancer properties. We performed a phase I study to determine the safety and maximum tolerated dose (MTD) of selinexor when combined with high-dose dexamethasone, ifosfamide, carboplatin and etoposide (DICE) in relapsed/refractory (R/R) T-cell lymphoma (TCL) and natural-killer/T-cell lymphoma (NKTL). Patients with R/R TCL and NKTL were treated with standard dose ICE, dexamethasone 20mg on days 3 to 7, and escalating doses of oral selinexor on days 3, 5 and 7 in a 3+3 design. Dose level (DL) 1, 2 and 3 were 40, 60 and 80mg respectively. Eleven patients with a median age of 60 were enrolled; 6 at DL1 and 5 at DL2. Patients had received a median of 2 (range 1-4) prior lines of treatment and 7 had primary refractory disease at study entry. Patients received a median of 3 cycles (range 1-6) of selinexor-DICE. The most common grade (G) 1/2 toxicities included nausea (64%), fatigue (55%), and anorexia (45%) and the most common G 3/4 toxicities included thrombocytopenia (82%), anemia (82%), neutropenia (73%), and hyponatremia (73%). Two patients developed doselimiting toxicities at DL2 and one at DL1. Five patients discontinued treatment for reasons other than disease progression or lack of response. Of the 10 evaluable patients, the overall and complete response rates were 91% and 82% respectively. The MTD of selinexor was 40mg when combined with DICE. The combination showed promising CR rates in patients with R/R TCL and NKTL but was poorly tolerated.

Clinical features and survival outcomes of ocular melanoma in a multi-ethnic Asian cohort.

Ocular melanomas are uncommon cancers in Southeast Asia unlike in the West. We conducted a retrospective review of patients (n = 44) with histologically-proven ocular melanoma within a multi-ethnic Asian cohort from Singapore. Clinicopathological features and relapse patterns were examined, and survival outcomes of interest included recurrence-free survival (RFS) and overall survival (OS). Survival analysis was performed using the Kaplan-Meier method and multivariable Cox proportional regression. The study cohort included 18 male and 26 female patients, with a median age of 52 years (range 8-78). Median follow-up was 154 months. For uveal melanomas (n = 29), the 5-year RFS and OS was 56.8% and 76.6%, respectively; whilst for conjunctival melanomas (n = 15), the 5-year RFS and OS was 30.1% and 68.8%, respectively. Fifteen patients (38.5%) eventually developed metastasis, following which the median survival was only 17 months. Multivariate analysis demonstrated that higher T stage was a significant independent predictor for both OS (HR 8.69, 95% CI 1.03 to 73.09, p = 0.047) and RFS (HR 11.62, 95% CI 2.45 to 55.00, p = 0.002). Smoking history was independently predictive of better RFS (HR 0.08, 95% CI 0.01 to 0.78, p = 0.030). In conclusion, our study demonstrates the poor ocular melanoma outcomes in Southeast Asians, highlighting the necessity for urgent research in this area of unmet clinical need.

Clinical Features of Plasmablastic Lymphoma: Case Series From an Asian Tertiary Cancer Center and Literature Review.

BACKGROUND: Plasmablastic lymphoma (PBL) is an aggressive subtype of mature B-cell non-Hodgkin lymphoma. Given its rarity, there remains a lack of clinicopathological data to guide its management, particularly on Asian patients. METHODS: We conducted a retrospective chart review of 10 patients diagnosed with PBL at the National Cancer Centre Singapore and performed a literature review of similar studies on Asian cohorts. RESULTS: Most patients were male (n = 9), with median age at diagnosis of 55 years (range, 33 - 91 years). Seven (70%) patients were considered to be immunocompromised. In the overall cohort, the median overall survival (OS) was 19.4 months with 5-year survival estimates given at 60% and 36% for OS and progression-free survival (PFS), respectively. At diagnosis, patients with HIV/AIDS (n = 5) were younger compared to others (median, 43 vs. 61 years; P = 0.0278), had greater number of nodal site involvement (median, 6 vs. 0; P = 0.0333), and higher international prognostic index (IPI) scores (P = 0.034 for trend). Amongst different chemotherapy used, etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin (EPOCH)-based regimens (n = 6) elicited prominent complete response rates (83%) and led to durable responses even in the setting of advanced stage, high-risk IPI score and immunodeficiency. CONCLUSIONS: In conclusion, our study describes the features of PBL in an Asian cohort and highlights disease features unique to HIV-associated PBL.