Whole exome sequencing and rare variant association study to identify genetic modifiers, KLF1 mutations, and a novel double mutation in Thai patients with hemoglobin E/beta-thalassemia.

OBJECTIVES: Clinical manifestations of patients with Hemoglobin E/beta-thalassemia vary from mild to severe phenotypes despite exhibiting the same genotype. Studies have partially identified genetic modifiers. We aimed to study the association between rare variants in protein-coding regions and clinical severity in Thai patients. METHODS: From April to November 2018, a case-control study was conducted based on clinical information and DNA samples collected from Thai patients with hemoglobin E/beta-thalassemia over the age of four years. Cases were patients with severe symptoms, while patients with mild symptoms acted as controls. Whole exome sequencing and rare variant association study were used to analyze the data. RESULTS: All 338 unrelated patients were classified into 165 severe and 173 mild cases. Genotypes comprised 81.4% of hemoglobin E/beta-thalassemia, 2.7% of homozygous or compound heterozygous beta-thalassemia, and 0.3% of (뫧)0 thalassemia Hb E while 15.7% of samples were not classified as beta-thalassemia. A novel cis heterozygotes of IVS I-7 (A > T) and codon 26 (G > A) was identified. Six genes (COL4A3, DLK1, FAM186A, PZP, THPO, and TRIM51) showed the strongest associations with severity (observed p-values of <0.05; significance lost after correction for multiplicity). Among known modifiers, KLF1 variants were found in four mild patients and one severe patient. CONCLUSION: No rare variants were identified as contributors to the clinical heterogeneity of hemoglobin E/beta-thalassemia. KLF1 mutations are potential genetic modifiers. Studies to identify genetic factors are still important and helpful for predicting severity and developing targeted therapy.

An urgent need for improving thalassemia care due to the wide gap in current real-life practice and clinical practice guidelines.

Based on Thalassemia International Federation clinical practice guidelines (CPG) for non-transfusion dependent and transfusion dependent thalassemia, several measures should be routinely implemented such as monitoring and surveillance of thalassemia related complications for early detection and proper clinical management. To evaluate the prevalence and the performance of routine surveillance for thalassemia related complications during 2 periods; before and after published CPGs (2012-2014 vs 2015-2017), data from 524 adult thalassemia patients attended at Siriraj hospital were compared among different treating physician groups; thalassemia, private hematology, and internal medicine clinics. Three most common complications were osteopenia/osteoporosis (69.8%), gallstones (67.6%) and abnormal vitamin D level (67.6%). Iron overload has been widely evaluated (93.1%) followed by liver function test (82.3%). However, the rate of evaluation for other complications were significantly reduced and < 25% of patients were evaluated in several complications. Comparing among clinics, the surveillance rate has increased significantly for several endocrine complications only in patients treated at thalassemia clinic but not in others. This study was the first study that evaluated real-world practical management of thalassemia patient in terms of complication surveillance. This different clinical practice has called for an immediate policy change to improve and standardize a care for thalassemia patients in Thailand.

Exploring health-related quality of life among non-Hodgkin's lymphoma survivors after completion of primary treatment: a cross-sectional study in Thailand.

PURPOSES: To investigate health-related quality of life (HR-QoL) and its influencing factors among non-Hodgkin's lymphoma (NHL) survivors after completion of primary treatment. METHODS: A cross-sectional study with 312 NHL survivors after completing primary treatment using self-reported data collected through face-to-face interviews or postal survey between May 2019 and December 2019. Sociodemographic factors, clinical characteristics, physical symptom distress, anxiety, depression, unmet supportive care needs, and adaptation (post-traumatic growth and post-traumatic stress disorder) were assessed. Data analysis included ANOVA tests to investigate HR-QoL among NHL survivors at different time points and GEE to assess predictors of HR-QoL. RESULTS: The mean score of HR-QoL was 136.05 (SD 19.12). HR-QoL scores reported by NHL survivors in phase I (6 months or less post-treatment) were significantly lower than those in phase II (> 6 months-4 years), phase III (> 4-9 years), and phase IV (over 9 years post-treatment). Regarding HR-QoL domains, NHL survivors in phase I had significantly lower physical well-being and functional well-being scores than those in phases II, III, and IV; and significantly lower lymphoma domain score than those in phase III. GEE analysis showed that physical symptom distress, anxiety, depression, unmet supportive care needs, poor adaptation, and receiving chemotherapy disrupted HR-QoL (all P < .001). CONCLUSIONS: Healthcare providers should re-prioritize intervention guidelines and survivorship care planning to promote HR-QoL among NHL survivors, particularly in phase I, through reducing physical and psychological symptom distress, addressing unmet needs, and enhancing adaptation outcomes.

Curcuminoids supplementation ameliorates iron overload, oxidative stress, hypercoagulability, and inflammation in non-transfusion-dependent ß-thalassemia/Hb E patients.

Curcuminoids, polyphenol compounds in turmeric, possess several pharmacological properties including antioxidant, iron-chelating, and anti-inflammatory activities. Effects of curcuminoids in thalassemia patients have been explored in a limited number of studies using different doses of curcuminoids. The present study aims to evaluate the effects of 24-week curcuminoids supplementation at the dosage of 500 and 1000 mg/day on iron overload, oxidative stress, hypercoagulability, and inflammation in non-transfused ß-thalassemia/Hb E patients. In general, both curcuminoids dosages significantly lowered the levels of oxidative stress, hypercoagulability, and inflammatory markers in the patients. In contrast, reductions in iron parameter levels were more remarkable in the 1000 mg/day group. Subgroup analysis revealed that a marker of hypercoagulability was significantly decreased only in patients with baseline ferritin ≤ 1000 ng/ml independently of curcuminoids dosage. Moreover, the alleviation of iron loading parameters was more remarkable in patients with baseline ferritin > 1000 ng/ml who receive 1000 mg/day curcuminoids. On the other hand, the responses of oxidative stress markers were higher with 500 mg/day curcuminoids regardless of baseline ferritin levels. Our study suggests that baseline ferritin levels should be considered in the supplementation of curcuminoids and the appropriate curcuminoids dosage might differ according to the required therapeutic effect. Thai Clinical Trials Registry (TCTR): TCTR20200731003; July 31, 2020 "retrospectively registered".

Review of disease-related complications and management in adult patients with thalassemia: A multi-center study in Thailand.

Disease-related complications and management are different among patients with thalassemia. This study was aimed to review the prevalence, clinical risk factors for the complications and the management in patients with thalassemia in Thailand. A multicenter cross-sectional study was conducted in patients with thalassemia aged ≥ 18 years old. Thalassemia-related complications and management were reviewed. The clinical parameters significantly associated with the complications were analyzed by logistic regression methods. The prevalence of thalassemia-related complications was 100% in patients with transfusion-dependent thalassemia (TDT) and 58.8% in patients with non-transfusion-dependent thalassemia (NTDT). Advanced age was statistically associated with extramedullary hematopoiesis in both TDT and NTDT patients. Splenectomy was a significant risk factor for pulmonary hypertension in both groups of patients. Severe iron overload started earlier in patients with TDT than NTDT and was associated with diabetes mellitus (adjusted odds ratio (AOR) = 6.2, p-value = 0.02). Disease-related complications are more prevalent in patients with TDT than patients with NTDT. Splenectomy and advanced age were important risk factors for developing major complications in both groups. Early screening and management for specific disease-related complications should be considered in patients with thalassemia according to their clinical risk factors.

A systematic review and meta-analysis of the prevalence of thrombosis and bleeding at diagnosis of Philadelphia-negative myeloproliferative neoplasms.

BACKGROUND: Philadelphia (Ph) chromosome-negative myeloproliferative neoplasms (MPNs) are a heterogeneous group of hematopoietic stem cell clonal diseases. Most patients with MPN are asymptomatic at diagnosis although some of them suffer from constitutional symptoms. Thrombosis and bleeding can also be one of the initial manifestations although the reported prevalence varied considerably across the studies. This systematic review and meta-analysis was conducted with the aims to better understand the prevalence and characteristics of thrombosis and bleeding among patients with newly-diagnosed MPN. METHODS: Using a search strategy that included the terms for myeloproliferative neoplasms, thrombosis, and bleeding, two investigators independently searched for published articles indexed in the MEDLINE and EMBASE databases from inception to August 2018. The pooled prevalence was calculated using the DerSimonian-Laird random-effects model with a double arcsine transformation. RESULTS: A total of 29 cohort studies (8 prospective and 21 retrospective) with 13,436 patients with MPN were included into this meta-analysis. At diagnosis, the pooled prevalence of overall thrombosis among patients with MPN was 20.0% (95% CI, 16.6-23.8%; I2 96%), with the pooled prevalence of arterial thrombosis of 16.2% (95% CI, 13.0-20.0%; I2 95%) and the pooled prevalence of venous thrombosis of 6.2% (95% CI, 4.9-7.8%; I2 89%). Common thrombotic events included cerebrovascular disease/transient ischemic attack, coronary heart disease, and deep venous thrombosis. The pooled prevalence of hemorrhagic complications among patients who were newly diagnosed with MPN patients was 6.2% (95% CI, 5.0-7.8%; I2 85%). Common sites of bleeding included gastrointestinal, mucosal, and cutaneous bleeding. CONCLUSIONS: Thrombosis and bleeding are common initial manifestations of MPN. Investigations for MPN should be considered for patients who present with unexplained thrombosis or abnormal bleeding.

Association between bortezomib dose intensity and overall survival in mantle cell lymphoma patients on frontline VR-CAP in the phase 3 LYM-3002 study.

The pivotal LYM-3002 study compared frontline rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) with bortezomib, rituximab, cyclophosphamide, doxorubicin and prednisone (VR-CAP) in newly diagnosed mantle cell lymphoma (MCL) patients for whom stem cell transplantation was not an option. This post hoc subanalysis of the VR-CAP data from LYM-3002 evaluated the effect of bortezomib dose intensity on OS in patients who completed ≥6 cycles of treatment. From the end of cycle 6, patients receiving ≥4.6 mg/m2/cycle of bortezomib had significantly longer OS (but not PFS) compared with those receiving <4.6 mg/m2/cycle by univariate analysis (HR 0.43 [95% CI: 0.23-0.80]; p = .0059). This association remained significant in multivariate analysis adjusting for baseline patient and disease characteristics (HR 0.40 [95% CI: 0.20-0.79]; p = .008]. Higher bortezomib dose intensity was the strongest predictor of OS in newly diagnosed MCL patients receiving VR-CAP. Clinicaltrials.gov identifier: NCT00722137.

Frontline bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) versus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in transplantation-ineligible patients with newly diagnosed mantle cell lymphoma: final overall survival results of a randomised, open-label, phase 3 study.

BACKGROUND: In the LYM-3002 study, the efficacy and safety of frontline bortezomib plus rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) and rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) were compared in transplant-ineligible patients with untreated, newly diagnosed, mantle cell lymphoma. We report the final overall survival and safety outcomes for patients in the long-term follow-up phase after the primary progression-free-survival endpoint was met. METHODS: LYM-3002 was a randomised, open-label, phase 3 study done at 128 clinical centres in 28 countries in Asia, Europe, North America, and South America. Adult patients with confirmed stage II-IV previously untreated mantle cell lymphoma, Eastern Cooperative Oncology Group performance status score of 2 or less, who were ineligible for bone marrow transplantation, were randomly assigned (1:1) to receive six or eight 21-day cycles of VR-CAP (intravenous rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and bortezomib 1·3 mg/m2, plus oral prednisone 100 mg/m2) or R-CHOP (intravenous vincristine 1·4 mg/m2 [2 mg maximum], rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, and doxorubicin 50 mg/m2, plus oral prednisone 100 mg/m2). Randomisation was done according to a computer-generated randomisation schedule prepared by the sponsor; permuted blocks central randomisation was used (block size of 4), and was stratified by International Prognostic Index score and disease stage at diagnosis. The primary endpoint of this final analysis was overall survival, which was analysed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00722137, and is closed to new participants with follow-up completed. FINDINGS: Between May 22, 2008, and Dec 5, 2011, 487 patients were enrolled and randomly assigned. 268 patients (140 in the VR-CAP group and 128 in the R-CHOP group) were included in the follow-up analysis, which included patients with data available after the primary analysis clinical cutoff date of Dec 2, 2013. After median follow-up of 82·0 months (IQR 74·1-94·2), median overall survival was significantly longer in the VR-CAP group than in the R-CHOP group (90·7 months [95% CI 71·4 to not estimable] vs 55·7 months [47·2 to 68·9]; hazard ratio 0·66 [95% CI 0·51-0·85]; p=0·001). Three new adverse events were reported since the primary analysis cutoff (one each of grade 4 lung adenocarcinoma and grade 4 gastric cancer in the VR-CAP group, and one case of grade 2 pneumonia in the R-CHOP group). 103 (42%) of 243 patients in the VR-CAP group, and 138 (57%) of 244 in the R-CHOP group died; the most common cause of death was progressive disease. INTERPRETATIONS: Compared with R-CHOP, VR-CAP was associated with significantly longer survival, and had a manageable and expected safety profile. Our results support further assessment of VR-CAP in patients with previously untreated mantle cell lymphoma. FUNDING: Janssen Research & Development.

Prospective study of brentuximab vedotin in relapsed/refractory Hodgkin lymphoma patients who are not suitable for stem cell transplant or multi-agent chemotherapy.

Some patients with relapsed/refractory Hodgkin lymphoma (HL) are not considered suitable for stem cell transplant (SCT) and have a poor prognosis. This phase IV study (NCT01990534) evaluated brentuximab vedotin (1·8 mg/kg intravenously once every 3 weeks) in 60 patients (aged ≥18 years) with CD30-positive relapsed/refractory HL, a history of ≥1 prior systemic chemotherapy regimen, who were considered unsuitable for SCT/multi-agent chemotherapy. Primary endpoint was overall response rate (ORR) per independent review facility (IRF). Secondary endpoints included duration of response (DOR), progression-free survival (PFS) per IRF, overall survival (OS), proportion proceeding to SCT and safety. The ORR was 50%, with 12% CR; 47% proceeded to SCT. Median DOR was 4·6 months and median duration of CR was 6·1 months. After a median follow-up of 6·9 and 16·6 months, median PFS and OS were 4·8 months (95% confidence interval, 3·0-5·3) and not reached, respectively; estimated OS rate was 86% at 12 months. Most common adverse events (≥10%) were peripheral neuropathy (35%), pyrexia (18%), diarrhoea and neutropenia (each 10%). Brentuximab vedotin showed notable activity with a safety profile consistent with known toxicities, and may act as a bridge to SCT, enabling high-risk patients who achieve suboptimal response to frontline/salvage chemotherapy/radiotherapy to receive potentially curative SCT.

High proportion of TAFRO syndrome in Thai adult Castleman's disease patients: a 10-year experience.

Castleman's disease (CD) is a rare lymphoproliferative disorder, and its prevalence in Thailand is not known. This 10-year period study investigated the prevalence of CD in Thailand, and the clinical characteristics and outcomes of Thai CD patients, with special focus on the existence and prevalence of TAFRO syndrome. TAFRO syndrome is defined as CD with thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly. Thirty-three CD patients diagnosed and treated at Siriraj Hospital during January 2007 to December 2016 were included. The prevalence of CD was 1.4 per 1,000,000 patients/10 years. Median age was 46 years, with slight female predominance. Six patients were assigned to the TAFRO group. A high proportion of TAFRO syndrome (18.2%) was found among Thai adult CD patients. In addition to routine TAFRO diagnostic criteria, significantly lower hemoglobin and albumin levels were observed in the TAFRO group than in the non-TAFRO group. Treatment outcomes of CD patients were complete remission (52%), stable disease (30%), and death (13%). Three-year overall survival in the non-TAFRO group and TAFRO group was 88 and 50%, respectively. While most CD patients had a good prognosis, severe cases with TAFRO syndrome had poor outcome.

A prospective analysis for prevalence of complications in Thai nontransfusion-dependent Hb E/ß-thalassemia and α-thalassemia (Hb H disease).

Recently, complications in patients with nontransfusion-dependent thalassemia (NTDT), in particular those with ß-thalassemia intermedia (ß-TI), were found to be significantly different from those in patients with transfusion dependent thalassemia (TDT), mainly ß-thalassemia major (ß-TM). However, this information is rather limited in other forms of NTDT. In this prospective study, adult Thai NTDT patients were interviewed and clinically evaluated for thalassemia related complications. Fifty-seven NTDT patients (age 18-74 years), 59.6% Hb E/ß-thalassemia and 40.4% Hb H disease, were recruited; 26.4% were splenectomized. The most common complications were gallstones (68.4%), osteoporosis (26.3%), and pulmonary hypertension (15.8%). Splenectomy was associated with higher rate of gallstones and serious infection (P = .001 and .052, respectively), consistent with a multivariate analysis (RR = 9.5, P = .044, and RR = 15.1, P = .043, respectively). In addition, a higher hemoglobin level was inversely associated with gallstones in both univariate and multivariate analyses (P = .01 and .022, respectively). Serum ferritin was associated with abnormal liver function (P = .002). In contrast to the previous study, the prevalence of thrombosis was less common in our population (1.7%), probably due to differences in transfusion therapy, ethnicity, and underlying genotypes. For the first time, this prospective study provided the current prevalence of NTDT related complications in a Southeast Asian population with a different underlying genetic basis compared with previous studies. Although individual prevalence of each complication might differ from other studies, several important clinical factors such as splenectomy, degree of anemia, and iron overload seem to be determining risks of developing these complications consistently across different ethnicities.

Quantitative proteomics of plasma vesicles identify novel biomarkers for hemoglobin E/ß-thalassemic patients.

Hemoglobin E (HbE)/ß-thalassemia has a wide spectrum of clinical manifestations that cannot be explained purely by its genetic background. Circulating extracellular vesicles (EVs) are one factor that likely contributes to disease severity. This study has explored the differences in protein composition and quantity between EVs from HbE/ß-thalassemic patients and healthy individuals. We used tandem mass tag labeling mass spectrometry to analyze the EV proteins isolated from the plasma of 15 patients compared with the controls. To reduce biological variation between individuals, the EV proteins isolated from randomly assigned groups of 5 HbE/ß-thalassemic patients were pooled and compared with 5 pooled age- and sex-matched controls in 3 separate experiments. Alpha hemoglobin-stabilizing protein had the highest fold increase. Catalase, superoxide dismutase, T-complex proteins, heat shock proteins, transferrin receptor, ferritin, and cathepsin S were also upregulated in thalassemic circulating EVs. Importantly, haptoglobin and hemopexin were consistently reduced in patients' EVs across all data sets, in keeping with the existing hemolysis that occurs in thalassemia. The proteomic data analysis of EV samples isolated from 6 individual HbE/ß-thalassemic patients and western blotting results corroborated these findings. In conclusion, we have successfully identified consistent alterations of protein quantity between EVs from HbE/ß-thalassemic and healthy individuals. This work highlights haptoglobin, hemopexin, and cathepsin S as potential clinically relevant biomarkers for levels of hemolysis and inflammation. Monitoring of these plasma proteins could help in the clinical management of thalassemia.

Prevalence and predictors of cardiac and liver iron overload in patients with thalassemia: A multicenter study based on real-world data.

Prevalence of cardiac and liver iron overload in patients with thalassemia in real-world practice may vary among different regions especially in the era of widely-used iron chelation therapy. The aim of this study was to determine the prevalence of cardiac and liver iron overload in and the management patterns of patients with thalassemia in real-world practice in Thailand. We established a multicenter registry for patients with thalassemia who underwent magnetic resonance imaging (MRI) as part of their clinical evaluation. All enrolled patients underwent cardiac and liver MRI for assessment of iron overload. There were a total of 405 patients enrolled in this study. The mean age of patients was 18.8±12.5years and 46.7% were male. Two hundred ninety-six (73.1%) of patients received regular blood transfusion. Prevalence of cardiac iron overload (CIO) and liver iron overload (LIO) was 5.2% and 56.8%, respectively. Independent predictors for iron overload from laboratory information were serum ferritin and transaminase for both CIO and LIO. Serum ferritin can be used as a screening tool to rule-out CIO and to diagnose LIO. Iron chelation therapy was given in 74.6%; 15.3% as a combination therapy.

Panobinostat plus bortezomib and dexamethasone: impact of dose intensity and administration frequency on safety in the PANORAMA 1 trial.

Panobinostat in combination with bortezomib and dexamethasone demonstrated a significant and clinically meaningful progression-free survival benefit compared with placebo, bortezomib and dexamethasone in the phase 3 PANORAMA 1 (Panobinostat Oral in Multiple Myeloma 1) trial. Despite this benefit, patients in the panobinostat arm experienced higher rates of adverse events (AEs) and higher rates of discontinuation due to AEs. This PANORAMA 1 subanalysis examined AEs between 2 treatment phases of the study (TP1 and TP2), in which administration frequency of bortezomib and dexamethasone differed per protocol. The incidences of several key AEs were lower in both arms following the planned reduction of bortezomib dosing frequency in TP2. In the panobinostat arm, rates of thrombocytopenia (grade 3/4: TP1, 56·7%; TP2, 6·0%), diarrhoea (grade 3/4: TP1, 24·1%; TP2, 7·1%), and fatigue (grade 3/4: TP1, 16·3%; TP2, 1·8%) were lower in TP2 compared with TP1. Dose intensity analysis of panobinostat and bortezomib by cycle in the panobinostat arm showed reductions of both agent doses during cycles 1-4 due to dose adjustments for AEs. Exposure-adjusted analysis demonstrated a reduction in thrombocytopenia frequency in TP1 following dose adjustment. These results suggest that optimization of dosing with this regimen could improve tolerability, potentially leading to improved patient outcomes.

Efficacy and safety of subcutaneous rituximab versus intravenous rituximab for first-line treatment of follicular lymphoma (SABRINA): a randomised, open-label, phase 3 trial.

BACKGROUND: Intravenous rituximab is the standard of care in B-cell non-Hodgkin lymphoma, and is administered over 1·5-6 h. A subcutaneous formulation could reduce patients' treatment burden and improve resource utilisation in health care. We aimed to show the pharmacokinetic non-inferiority of subcutaneous rituximab to intravenous rituximab in follicular lymphoma and to provide efficacy and safety data. METHODS: SABRINA is a two-stage, randomised, open-label phase 3 study at 113 centres in 30 countries. Eligible patients were aged 18 years or older and had histologically confirmed, previously untreated, CD20-positive grade 1, 2, or 3a follicular lymphoma; Eastern Co-operative Oncology Group performance statuses of 0-2; bidimensionally measurable disease (by CT or MRI); life expectancy of 6 months or more; adequate haematological function for 28 days or more; and one or more symptoms requiring treatment according to the Groupe d'Etudes des Lymphomes Folliculaires criteria. Patients were randomly assigned (1:1) by investigators or members of the research team via a dynamic randomisation algorithm to 375 mg/m2 intravenous rituximab or 1400 mg subcutaneous rituximab, plus chemotherapy (six-to-eight cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP] or eight cycles of cyclophosphamide, vincristine, and prednisone [CVP]), every 3 weeks during induction, then rituximab maintenance every 8 weeks. Randomisation was stratified by selected chemotherapy, Follicular Lymphoma International Prognostic Index, and region. The primary endpoint for stage 2 was overall response (ie, confirmed complete response, unconfirmed complete response, and partial response) at the end of induction. Efficacy analyses were done in the intention-to-treat population. Pooled data from stages 1 and 2 are reported on the basis of the clinical cutoff date of the last patient completing the maintenance phase of the study. This trial is registered with ClinicalTrials.gov, number NCT01200758; new patients are no longer being recruited, but some patients are still being followed up. FINDINGS: Between Feb 15, 2011, and May 15, 2013, 410 patients were randomly assigned, 205 to intravenous rituximab and 205 to subcutaneous rituximab. Investigator-assessed overall response at the end of induction was 84·9% (95% CI 79·2-89·5) in the intravenous group and 84·4% (78·7-89·1) in the subcutaneous group. The frequency of adverse events was similar in both groups (199 [95%] of 210 in the intravenous group vs 189 [96%] of 197 in the subcutaneous group); the frequency of adverse events of grade 3 or higher was also similar (116 [55%] vs 111 [56%]). The most common grade 3 or higher adverse event was neutropenia, which occurred in 44 patients (21%) in the intravenous group and 52 (26%) in the subcutaneous group. Serious adverse events occurred in 72 patients (34%) in the intravenous group and 73 (37%) in the subcutaneous group. Administration-related reactions occurred in 73 patients (35%) in the intravenous group and 95 (48%) patients in the subcutaneous group (mainly grade 1 or 2 local injection-site reactions). INTERPRETATION: Intravenous and subcutaneous rituximab had similar efficacy and safety profiles, and no new safety concerns were noted. Subcutaneous administration does not compromise the anti-lymphoma activity of rituximab when given with chemotherapy. FUNDING: F Hoffmann-La Roche.

Association between quality of response and outcomes in patients with newly diagnosed mantle cell lymphoma receiving VR-CAP versus R-CHOP in the phase 3 LYM-3002 study.

In the phase 3 LYM-3002 study comparing intravenous VR-CAP with R-CHOP in patients with newly-diagnosed, measurable stage II-IV mantle cell lymphoma, not considered or ineligible for transplant, the median progression-free survival was significantly improved with VR-CAP (24.7 versus 14.4 months with R-CHOP; P<0.001). This post-hoc analysis evaluated the association between the improved outcomes and quality of responses achieved with VR-CAP versus R-CHOP in LYM-3002. Patients were randomized to six to eight 21-day cycles of VR-CAP or R-CHOP. Outcomes included progression-free survival, duration of response (both assessed by an independent review committee), and time to next anti-lymphoma treatment, evaluated by response (complete response/unconfirmed complete response and partial response), MIPI risk status, and maximum reduction of lymph-node measurements expressed as the sum of the product of the diameters. Within each response category, the median progression-free survival was longer for patients given VR-CAP than for those given R-CHOP (complete response/unconfirmed complete response: 40.9 versus 19.8 months; partial response: 17.1 versus 11.7 months, respectively); similarly, the median time to next anti-lymphoma treatment was longer among the patients given VR-CAP than among those treated with R-CHOP (complete response/unconfirmed complete response: not evaluable versus 26.6 months; partial response: 35.3 versus 24.3 months). Within the complete/unconfirmed complete and partial response categories, improvements in progression-free survival, duration of response and time to next anti-lymphoma treatment were more pronounced in patients with low-and intermediate-risk MIPI treated with VR-CAP than with R-CHOP. In each response category, more VR-CAP than R-CHOP patients had a sum of the product of the diameters nadir of 0 during serial radiological assessments. Results of this post-hoc analysis suggest a greater duration and quality of response in patients treated with VR-CAP in comparison with those treated with R-CHOP, with the improvements being more evident in patients with low- and intermediate-risk MIPI. LYM-3002 ClinicalTrials.gov: NCT00722137.

Overall survival of patients with relapsed multiple myeloma treated with panobinostat or placebo plus bortezomib and dexamethasone (the PANORAMA 1 trial): a randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Panobinostat plus bortezomib and dexamethasone significantly increased median progression-free survival compared with placebo plus bortezomib and dexamethasone in the phase 3 PANORAMA 1 trial. Here, we present the final overall survival analysis for this trial. METHODS: PANORAMA 1 is a randomised, placebo-controlled, double-blind, phase 3 trial of patients with relapsed or relapsed and refractory multiple myeloma with one to three previous treatments. Patients were randomly assigned (1:1) to receive panobinostat (20 mg orally) or placebo, with bortezomib (1·3 mg/m2 intravenously) and dexamethasone (20 mg orally), over two distinct treatment phases. In treatment phase 1 (eight 3-week cycles), patients received: panobinostat or placebo on days 1, 3, 5, 8, 10, and 12; bortezomib on days 1, 4, 8, and 11; and dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12. During treatment phase 2 (four 6-week cycles with a 2 weeks on, 1 week off schedule), panobinostat or placebo was given three times a week, bortezomib was administered once a week, and dexamethasone was given on the days of and following bortezomib administration. The primary endpoint was progression-free survival; overall survival was a key secondary endpoint. This study is registered at ClinicalTrials.gov, NCT01023308. FINDINGS: Between Jan 21, 2010, and Feb 29, 2012, 768 patients were enrolled into the study and randomly assigned to receive either panobinostat (n=387) or placebo (n=381), plus bortezomib and dexamethasone. At data cutoff (June 29, 2015), 415 patients had died. Median overall survival was 40·3 months (95% CI 35·0-44·8) in those who received panobinostat, bortezomib, and dexamethasone versus 35·8 months (29·0-40·6) in those who received placebo, bortezomib, and dexamethasone (hazard ratio [HR] 0·94, 95% CI 0·78-1·14; p=0·54). Of patients who had received at least two previous regimens including bortezomib and an immunomodulatory drug, median overall survival was 25·5 months (95% CI 19·6-34·3) in 73 patients who received panobinostat, bortezomib, and dexamethasone versus 19·5 months (14·1-32·5) in 74 who received placebo (HR 1·01, 95% CI 0·68-1·50). INTERPRETATION: The overall survival benefit with panobinostat over placebo with bortezomib and dexamethasone was modest. However, optimisation of the regimen could potentially prolong treatment duration and improve patients' outcomes, although further trials will be required to confirm this. FUNDING: Novartis Pharmaceuticals.

Optimising iron chelation therapy with deferasirox for non-transfusion-dependent thalassaemia patients: 1-year results from the THETIS study.

Efficacy and safety of iron chelation therapy with deferasirox in iron-overloaded non-transfusion-dependent thalassaemia (NTDT) patients were established in the THALASSA study. THETIS, an open-label, single-arm, multicentre, Phase IV study, added to this evidence by investigating earlier dose escalation by baseline liver iron concentration (LIC) (week 4: escalation according to baseline LIC; week 24: adjustment according to LIC response, maximum 30mg/kg/day). The primary efficacy endpoint was absolute change in LIC from baseline to week 52. 134 iron-overloaded non-transfusion-dependent anaemia patients were enrolled and received deferasirox starting at 10mg/kg/day. Mean actual dose±SD over 1year was 14.70±5.48mg/kg/day. At week 52, mean LIC±SD decreased significantly from 15.13±10.72mg Fe/g dw at baseline to 8.46±6.25mg Fe/g dw (absolute change from baseline, -6.68±7.02mg Fe/g dw [95% CI: -7.91, -5.45]; P<0.0001). Most common drug-related adverse events were gastrointestinal: abdominal discomfort, diarrhoea and nausea (n=6 each). There was one death (pneumonia, not considered drug related). With significant and clinically relevant reductions in iron burden alongside a safety profile similar to that in THALASSA, these data support earlier escalation with higher deferasirox doses in iron-overloaded non-transfusion-dependent anaemia patients.