Noppadol Siritanaratkul

Bortezomib-based therapy for newly diagnosed mantle-cell lymphoma.

BACKGROUND The proteasome inhibitor bortezomib was initially approved for the treatment of relapsed mantle-cell lymphoma. We investigated whether substituting bortezomib for vincristine in frontline therapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) could improve outcomes in patients with newly diagnosed mantle-cell lymphoma. METHODS In this phase 3 trial, we randomly assigned 487 adults with newly diagnosed mantle-cell lymphoma who were ineligible or not considered for stem-cell transplantation to receive six to eight 21-day cycles of R-CHOP intravenously on day 1 (with prednisone administered orally on days 1 to 5) or VR-CAP (R-CHOP regimen, but replacing vincristine with bortezomib at a dose of 1.3 mg per square meter of body-surface area on days 1, 4, 8, and 11). The primary end point was progression-free survival. RESULTS After a median follow-up of 40 months, median progression-free survival (according to independent radiologic review) was 14.4 months in the R-CHOP group versus 24.7 months in the VR-CAP group (hazard ratio favoring the VR-CAP group, 0.63; P<0.001), a relative improvement of 59%. On the basis of investigator assessment, the median durations of progression-free survival were 16.1 months and 30.7 months, respectively (hazard ratio, 0.51; P<0.001), a relative improvement of 96%. Secondary end points were consistently improved in the VR-CAP group, including the complete response rate (42% vs. 53%), the median duration of complete response (18.0 months vs. 42.1 months), the median treatment-free interval (20.5 months vs. 40.6 months), and the 4-year overall survival rate (54% vs. 64%). Rates of neutropenia and thrombocytopenia were higher in the VR-CAP group. CONCLUSIONS VR-CAP was more effective than R-CHOP in patients with newly diagnosed mantle-cell lymphoma but at the cost of increased hematologic toxicity. (Funded by Janssen Research and Development and Millennium Pharmaceuticals; LYM-3002 ClinicalTrials.gov number, NCT00722137.).

Clinical manifestation of beta-thalassemia/hemoglobin E disease.

Purpose To review the clinical manifestation and changes in hematologic parameters of patients with &bgr;-thalassemia/hemoglobin (Hb) E. Materials and Methods Retrospective analysis of the clinical manifestation of 378 patients with &bgr;-thalassemia/Hb E attending the hematology clinic at Siriraj Hospital between 1957 and 1982. Results A wide spectrum of clinical phenotypes has been observed. Most patients show clinical symptoms by 10 years of age. The majority of patients survive with or without occasional transfusion. Splenectomy was performed in 26.5% of patients. Patients come to the hospital because of anemia, fever, abdominal mass, and jaundice. Gastrointestinal tract disturbances are the most common presenting symptoms (34.6%), especially abdominal pain (10%) and cholecystitis (5.1%). Respiratory tract infections were found in 21.8% of patients and cardiovascular complications, including congestive heart failure, occurred in 11.9%. Other less common symptoms and complications included bone pain, chronic leg ulcers, paraplegia and hypertension-associated convulsions, and cerebral hemorrhage after multiple blood transfusion. Patients usually die between 20 to 40 years of age (67%), mainly from congestive heart failure and septicemia. Septicemia was often caused by Gram-negative bacteria. Conclusion These clinical features observed in patients with &bgr;-thalassemia/Hb E are probably the results of chronic anemia and iron overload. The study of the life history and clinical courses of patients with &bgr;-thalassemia/Hb E should provide important information for the better management of these patients.

Deferasirox reduces iron overload significantly in nontransfusion-dependent thalassemia: 1-year results from a prospective, randomized, double-blind, placebo-controlled study

Nontransfusion-dependent thalassemia (NTDT) patients may develop iron overload and its associated complications despite receiving only occasional or no transfusions. The present 1-year, randomized, double-blind, placebo-controlled THALASSA (Assessment of Exjade in Nontransfusion-Dependent Thalassemia) trial assessed the efficacy and safety of deferasirox in iron-overloaded NTDT patients. A total of 166 patients were randomized in a 2:1:2:1 ratio to starting doses of 5 or 10 mg/kg/d of deferasirox or placebo. The means ± SD of the actual deferasirox doses received over the duration of the study in the 5 and 10 mg/kg/d starting dose cohorts were 5.7 ± 1.4 and 11.5 ± 2.9 mg/kg/d, respectively. At 1 year, the liver iron concentration (LIC) decreased significantly compared with placebo (least-squares mean [LSM] ± SEM, -2.33 ± 0.7 mg Fe/g dry weight [dw], P = .001, and -4.18 ± 0.69 mg Fe/g dw, P < .001) for the 5 and 10 mg/kg/d deferasirox groups, respectively (baseline values [means ± SD], 13.11 ± 7.29 and 14.56 ± 7.92 mg Fe/g dw, respectively). Similarly, serum ferritin decreased significantly compared with placebo by LSM -235 and -337 ng/mL for the deferasirox 5 and 10 mg/kg/d groups, respectively (P < .001). In the placebo patients, LIC and serum ferritin increased from baseline by 0.38 mg Fe/g dw and 115 ng/mL (LSM), respectively. The most common drug-related adverse events were nausea (n = 11; 6.6%), rash (n = 8; 4.8%), and diarrhea (n = 6; 3.6%). This is the first randomized study showing that iron chelation with deferasirox significantly reduces iron overload in NTDT patients with a frequency of overall adverse events similar to placebo.

Activated platelet-derived microparticles in thalassaemia.

Thromboembolic complications have been documented in thalassaemia patients. The aggregability of abnormal red blood cells and the high level of membrane‐derived microparticles (MPs) stemming from blood cells are thought to be responsible for the associated thrombotic risk. We investigated the number of MPs, their cellular origin and their procoagulant properties in β‐thalassaemia. Fresh whole blood was simultaneously stained for annexin V, cellular antigens and the known density beads. The procoagulant properties of these phosphatidylserine (PS)‐bearing MPs were also measured by assessing the platelet factor‐3‐like activity in the blood. Flow cytometric results showed that splenectomised β‐thalassaemia/HbE patients had significantly higher levels of PS‐bearing MPs than non‐splenectomised β‐thalassaemia/HbE patients and normal individuals (P < 0·0001). There was a good correlation between PS‐bearing MPs and PS‐bearing platelets, reflecting the existence of chronic platelet activation in β‐thalassaemia/HbE patients (rs = 0·511, P < 0·001). The cellular origin of PS‐bearing MPs showed mostly activated‐platelet origin with adhesion (CD41a/CD62P/CD36). Moreover, the platelet procoagulant activity was higher in splenectomised β‐thalassaemia/HbE patients when compared with non‐splenectomised (P < 0·05) and normal individuals (P < 0·01), and the amount correlated with PS‐bearing MPs (rs = 0·560, P < 0·001). These findings suggest that MPs originate from activated platelets with a potential to aggravate thrombotic events when the numbers are excessive, as is commonly seen in splenectomised β‐thalassaemia/HbE patients.

Panobinostat plus bortezomib and dexamethasone in previously treated multiple myeloma: outcomes by prior treatment

Panobinostat is a potent pan-deacetylase inhibitor that affects the growth and survival of multiple myeloma (MM) cells through alteration of epigenetic mechanisms and protein metabolism. Panobinostat plus bortezomib and dexamethasone (PAN-BTZ-Dex) led to a significant increase in progression-free survival (PFS) vs placebo plus bortezomib and dexamethasone (Pbo-BTZ-Dex) in patients with relapsed or relapsed and refractory MM in the phase 3 PANORAMA 1 trial. This subgroup analysis evaluated outcomes in patients in the PANORAMA 1 trial based on prior treatment: a prior immunomodulatory drug (IMiD; n = 485), prior bortezomib plus an IMiD (n = 193), and ≥2 prior regimens including bortezomib and an IMiD (n = 147). Median PFS with PAN-BTZ-Dex vs Pbo-BTZ-Dex across subgroups was as follows: prior IMiD (12.3 vs 7.4 months; hazard ratio [HR], 0.54; 95% confidence interval [CI], 0.43-0.68), prior bortezomib plus IMiD (10.6 vs 5.8 months; HR, 0.52; 95% CI, 0.36-0.76), and ≥2 prior regimens including bortezomib and an IMiD (12.5 vs 4.7 months; HR, 0.47; 95% CI, 0.31-0.72). Common grade 3/4 adverse events and laboratory abnormalities in patients who received PAN-BTZ-Dex across the prior treatment groups included thrombocytopenia, lymphopenia, neutropenia, diarrhea, and asthenia/fatigue. Incidence of on-treatment deaths among patients who received prior bortezomib and an IMiD (regardless of number of prior regimens) was similar between treatment arms. This analysis demonstrated a clear PFS benefit of 7.8 months with PAN-BTZ-Dex among patients who received ≥2 prior regimens including bortezomib and an IMiD, a population with limited treatment options and poorer prognosis. This trial was registered at www.clinicaltrials.gov as #NCT01023308.

Improvement in oxidative stress and antioxidant parameters in β-thalassemia/Hb E patients treated with curcuminoids.

OBJECTIVES To evaluate the hematological profile, oxidative stress, and antioxidant parameters in beta-thalassemia/Hb E patients treated with curcuminoids for 12 months. DESIGN AND METHODS Twenty-one beta-thalassemia/Hb E patients were given 2 capsules of 250 mg each of curcuminoids (a total of 500 mg) daily for 12 months. Blood was collected every 2 months during treatment and 3 months after withdrawal and was determined for complete blood count, malonyldialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), reduced glutathione (GSH) in red blood cells (RBC), and non-transferrin bound iron (NTBI) in serum. RESULTS The increased oxidative stress in beta-thalassemia/Hb E patients was shown by higher levels of MDA, SOD, GSH-Px in RBC, serum NTBI, and lower level of RBC GSH. Curcuminoids administration resulted in improvement of all the measured parameters as long as they were administered. After 3 months withdrawal of treatment, all parameters returned close to baseline levels. CONCLUSION Curcuminoids may be used to ameliorate oxidative damage in patients with beta-thalassemia/Hb E disease.

Pharmacokinetics and safety of subcutaneous rituximab in follicular lymphoma (SABRINA): stage 1 analysis of a randomised phase 3 study

BACKGROUND Intravenous rituximab is a mainstay of treatment for follicular lymphoma. A subcutaneous formulation that achieves equivalent rituximab serum concentrations might improve convenience and save health-care resources without sacrificing clinical activity. We aimed to assess pharmacokinetic non-inferiority of 3 week cycles of fixed-dose subcutaneous rituximab versus standard intravenous rituximab. METHODS In our two-stage, randomised, open-label, phase 3 trial, we enrolled patients with previously untreated grade 1-3a, CD20-positive follicular lymphoma at 67 centres in 23 countries. In stage 1, we randomly allocated patients 1:1 with the Pocock and Simon algorithm to intravenous rituximab (375 mg/m(2)) or fixed-dose subcutaneous rituximab (1400 mg), stratified by induction chemotherapy regimen (cyclophosphamide, doxorubicin, vincristine, prednisone or cyclophosphamide, vincristine, prednisone), Follicular Lymphoma International Prognostic Index score, and region. After randomisation, patients received one induction dose of intravenous rituximab in cycle 1 and then allocated treatment for cycles 2-8. Patients with a complete or partial response following induction therapy continued intravenous or subcutaneous rituximab as maintenance every 8 weeks. The primary endpoint was the ratio of observed rituximab serum trough concentrations (Ctrough) between groups at cycle 7 (before cycle 8 dosing) of induction treatment in a per-protocol population. Patients were analysed as treated for safety endpoints. Stage 2 follow-up is ongoing and is fully accrued. This study is registered with ClinicalTrials.gov, number NCT01200758. FINDINGS Between Feb 4, 2010, and Oct 21, 2011, we enrolled 127 patients. Pharmacokinetic data were available for 48 (75%) of 64 patients randomly allocated intravenous rituximab and 54 (86%) of 63 patients randomly allocated subcutaneous rituximab. Geometric mean Ctrough was 83·13 μg/mL in the intravenous group and 134·58 μg/mL in the subcutaneous group (ratio 1·62, 90% CI 1·36-1·94), showing non-inferiority of subcutaneous rituximab. 57 (88%) of 65 patients in the intravenous rituximab safety population had adverse events (30 [46%] grade ≥3), as did 57 (92%) of 62 patients in the subcutaneous rituximab safety population (29 [47%] grade ≥3). The most common grade 3 or worse adverse event in both groups was neutropenia (14 [22%] patients in the intravenous group and 16 [26%] patients in the subcutaneous group). Adverse events related to administration were mostly grade 1-2 and occurred in 21 (32%) patients in the intravenous group and 31 (50%) patients in the subcutaneous group. INTERPRETATION Stage 1 data show that the pharmacokinetic profile of subcutaneous rituximab was non-inferior to intravenous rituximab and was not associated with new safety concerns. Stage 2 will provide data for efficacy and safety of the subcutaneous administration. FUNDING F Hoffmann-La Roche.

Clofazimine-induced crystal-storing histiocytosis producing chronic abdominal pain in a leprosy patient.

Clofazimine-induced crystal-storing histiocytosis is a rare but well-recognized condition in the literature. Besides the common reddish discoloration of the skin, clofazimine produces gastrointestinal disturbances-sometimes severe abdominal pain, prompting exploratory laparotomy, because pathologic and radiologic findings can produce diagnostic difficulties if the pathologic changes caused by clofazimine are not recognized. The authors report such a case in a leprosy patient to emphasize the importance of history taking, the radiologic abnormalities of the small intestine, and the pathologic findings in small intestine and lymph node biopsies. Clofazimine crystals are red in the frozen section and exhibit bright-red birefringence. However, they are clear in routinely processed histologic sections because they dissolve in alcohol and organic solvents. They also appear as clear crystal spaces during electron microscopic study, but some osmiophilic bodies can be observed. Histiocytosis caused by clofazimine crystals produces infiltrative lesions in radiologic studies mimicking malignant lymphoma or other infiltrative disorders. Associated plasmacytosis in the histologic sections can simulate lymphoplasmacytic lymphoma or multiple myeloma with crystal-storing histiocytosis. With the knowledge of this rare condition caused by clofazimine, appropriate management to avoid an unnecessary laparotomy is possible.

Impaired interaction of α-haemoglobin-stabilising protein with α-globin termination mutant in a yeast two-hybrid system

α‐Thalassaemia caused by α‐globin gene termination codon mutations (αT‐globin) has been explained by their inherent mRNA instability and by oxidative damage arising from the presence of membrane‐bound αT‐globin chains. To better understand the latter phenomenon, a yeast two‐hybrid system was used to assay the interaction between αT‐globin and its molecular chaperone, α‐haemoglobin‐stabilising protein (AHSP) and impaired binding of αT‐globin with AHSP compared with αwild‐type‐globin was observed.

Clinical profiles of multiple myeloma in Asia—An Asian Myeloma Network study

The incidence of multiple myeloma (MM) is known to be variable according to ethnicity. However, the differences in clinical characteristics between ethnic groups are not well‐defined. In Asian countries, although the incidence of MM has been lower than that of Western countries, there is growing evidence that MM is increasing rapidly. The Asian Myeloma Network decided to initiate the first multinational project to describe the clinical characteristics of MM and the clinical practices in Asia. Data were retrospectively collected from 23 centers in 7 countries and regions. The clinical characteristics at diagnosis, survival rates and initial treatment of 3,405 symptomatic MM patients were described. Median age was 62 years (range, 19–106), with 55.6% of being male. Median overall survival (OS) was 47 months (95% CI 44.0–50.0). Stem cell transplantation was performed in 666 patients who showed better survival rates (79 vs. 41 months, P < 0.001). The first‐line treatments of 2,970 patients were analyzed. The overall response rate was 71% including very good partial response or better in 31% of the 2,660 patients those were able to be evaluated. New drugs including bortezomib, thalidomide, and lenalidomide were used in 36% of 2,970 patients and affected OS when used as a first‐line treatment. Am. J. Hematol. 89:751–756, 2014.