Event-free survival at 12 months is a strong surrogate endpoint for stage 1 diffuse large B cell lymphoma: a report from Nation Wide Registry Thai Lymphoma Study Group.

Event-free survival at 12 months (EFS12) is a surrogate endpoint for long-term outcomes in many histologic lymphoma subtypes. However, most reports have primarily investigated the implication of EFS12 in advanced-stage non-Hodgkin lymphoma (NHL). There are limited data regarding the significance of EFS12 in early-stage NHL. Herein, we evaluated the prognostic significance of EFS12 in patients with stage 1 diffuse large B-cell lymphoma (DLBCL). Out of 282 patients with stage 1 DLBCL who received intensive therapy, 227 (80.5%) achieved EFS12. The 4-year overall survival (OS) was 91.4% and 4.0% for patients who achieved and failed to achieve EFS12, respectively. Multivariable analyses demonstrated response to treatment and achievement of EFS12 as independent predictors for OS. In conclusion, our study demonstrated EFS12 as a powerful prognostic factor for stage 1 DLBCL. Further validation in more extensive prospective studies is warranted.

Characteristics, treatment patterns, prognostic determinants and outcome of peripheral T cell lymphoma and natural killer/T cell non-Hodgkin Lymphoma in older patients: The result of the nationwide multi-institutional registry Thai Lymphoma Study Group.

INTRODUCTION: Peripheral T cell NHL (PTCL) and natural killer/T cell NHL (NKTCL) are relatively rare disorders. Data on clinical presentation, treatment and outcome are limited especially in older age groups. METHODS: We identified 127 patients with PTCL and NKTCL, excluding cutaneous T/NK cell lymphoma, aged over 60 years old from Thailand nationwide multicenter registry. RESULTS: Of 127 patients, median age of diagnosis was 67 years old. Patients aged older than 75 years old had similar characteristics to younger (60-74 years old) but higher comorbidity index. Seventy-nine patients (62.2%) received intensive/definite multi-agent chemotherapy, however, the proportion was significant lower in older patients (70.4% vs 34.5%, p < .001). After a median follow up duration of 17.3 months, 2-year progression free survival and overall survival were 38.1% and 48.5%. Univariate and multivariable analysis demonstrated older age, poor performance status and absence of definite multi-agent chemotherapy were associated with inferior survival. Definite multi-agent lymphoma specific chemotherapy was an independent factor for overall survival after adjustment for age, comorbidity index, performance status and prognostic index for T cell lymphoma. CONCLUSION: Despite overall poor prognosis of PTCL and NKTCL in older adults, chemotherapy could result in objective response and long-term survival in selected patients of this vulnerable age group thus emphasizing the importance of comprehensive geriatric evaluation.

Event free survival at 24 months is a strong surrogate prognostic endpoint of peripheral T cell lymphoma.

Event free survival at 24 months (EFS24) has been described as a powerful predictor for outcome in several subtypes of B cell lymphoma. However, it was limitedly described in T cell lymphoma. We explored the implication of EFS24 as a predictor marker for peripheral T cell lymphoma (PTCL). We reviewed 293 systemic PTCL patients at 13 nationwide major university hospitals in Thailand from 2007 to 2014. The median event free survival (EFS) and overall survival (OS) of PTCL patients in our cohort was 16.3 and 27.7 months with corresponding 2-year EFS and 2-year OS of 45.8% and 51.9%, respectively. A total of 118 patients achieved EFS24 (no events during the first 24 mo). Patients who achieved EFS24 had better OS than patients who did not (2-y OS 92% vs 18.8%; HR, 0.1; P < .001). The standardized mortality ratio of patients achieving EFS24 was 18.7 (95% CI, 14.6-22.8). Multivariable analysis demonstrated performance status, histologic subtype, remission status, and EFS24 achievement as independent predictors for OS. Our study affirmed the value of EFS24 as a powerful prognostic factor for PTCL. Further validation in prospective study setting is warranted.

Survival differences in multiple myeloma in Latin America and Asia: a comparison involving 3664 patients from regional registries.

In previous observational studies, we have separately characterized patients with multiple myeloma (MM) both from Latin America (LA) and from Asia. Here, we analyze these two datasets jointly, in order to assess the overall survival (OS) in these two world regions. Data were available from 3664 patients (1968 from LA and 1696 from Asia); all of whom diagnosed between 1998 and 2007. Approximately, 26% of patients in both world regions underwent transplantation. OS (from diagnosis of MM) was explored with Kaplan-Meier analyses and Cox proportional hazards models. Patients from LA were significantly younger and had hypercalcemia more often than Asian patients, who in turn had higher proportions of anemia and International Staging System (ISS) stage III disease. The median OS was 56 months in LA, and 47 months in Asia (hazard ratio [HR] = 0.83; 95% confidence interval [CI], 0.76 to 0.91; P < 0.001). In multivariable analysis, age, ISS stage III, anemia, hypercalcemia, and world region remained significantly associated with OS (P < 0.001 for all covariates). These results were largely driven by patients not undergoing transplantation, as no difference in OS emerged between the two world regions in univariable or multivariable analysis for transplanted patients. Despite adverse prognostic features differentially favoring each region, and adjusting for such differences, we found an OS advantage for patients from LA, in comparison with contemporaneous patients from Asia. Whether this is due to different biological features, differences in access to novel agents (especially thalidomide in earlier periods of the study), unmeasured confounders, or the play of chance, remain unknown.

Recent advances in the management of multiple myeloma: clinical impact based on resource-stratification. Consensus statement of the Asian Myeloma Network at the 16th international myeloma workshop.

Predicated on our improved understanding of the disease biology, we have seen remarkable advances in the management of multiple myeloma over the past few years. Recently approved drugs have radically transformed the treatment paradigm and improved survivals of myeloma patients. The progress has necessitated revision of the diagnostic criteria, risk-stratification and response definition. The huge disparities in economy, healthcare infrastructure and access to novel drugs among different Asian countries will hinder the delivery of optimum myeloma care to patients managed in resource-constrained environments. In the light of the tremendous recent changes and evolution in myeloma management, it is timely that the resource-stratified guidelines from the Asian Myeloma Network be revised to provide updated recommendations for Asia physicians practicing under various healthcare reimbursement systems. This review will highlight the most recent advances and our recommendations on how they could be integrated in both resource-abundant and resource-constrained facilities.

Non-Hodgkin lymphoma in South East Asia: An analysis of the histopathology, clinical features, and survival from Thailand.

Systemic reports on the descriptive epidemiology of non-Hodgkin lymphoma (NHL) from Southeast Asia are scarce. A nationwide multi-institutional registry was conducted to compare the histopathology, clinical features, and survival of Thai adult patients with NHL using large registries, especially those from Far East Asia (FEA). Using a web-based registry system, 13 major medical centers from the 4 geographic regions of Thailand prospectively collected, from 2007 to 2014, the diagnostic pathology, according to the World Health Organization classification, 2008, clinical features and survival of 4056 patients who were newly diagnosed with NHL. The median age of the patients was 56 years (range, 16-99 years). The male-to-female ratio was 1.3:1. From the total of 4056 patients, T/NK-cell lymphoma (TNKCL) accounted for 12.6% of cases, and 5.1% had human immunodeficiency virus-associated lymphoma. The four leading histological subtypes were diffuse large B-cell lymphoma, not otherwise specified (58.1%); follicular lymphoma (5.6%); extranodal mucosa-associated lymphoid tissue lymphoma (5.2%); and peripheral T-cell lymphoma, not otherwise specified (4.0%). With a median follow-up duration of 46.1 months, the median overall survival of B-cell NHL was significantly longer than that of patients with TNKCL (76.5 vs 28.8 months, P = .0001). Compared to FEA, the Thai registry had an approximately one-half lower relative frequency of TNKCL; the prevalence of extranodal mucosa-associated lymphoid tissue lymphoma was much lower than in Korea, and the frequency of extranodal TNKCL, nasal type, was strikingly low compared to China. It is concluded that while the median age of Thai patients with NHL was approximately a decade younger than for Caucasians, the long-term survival rates for most histological subtypes were comparable. While the histological distribution generally complied with the characteristic Asian features, some differences from FEA were observed.

Secondary central nervous system relapse in diffuse large B cell lymphoma in a resource limited country: result from the Thailand nationwide multi-institutional registry.

Secondary central nervous system (CNS) relapse is a serious and fatal complication of diffuse large B cell lymphoma (DLBCL). Data on secondary CNS (SCNS) relapse were mostly obtained from western countries with limited data from developing countries. We analyzed the data of 2034 newly diagnosed DLBCL patients enrolled into the multi-center registry under Thai Lymphoma Study Group from setting. The incidence, September 2006 to December 2013 to represent outcome from a resource limited pattern, management, and outcome of SCNS relapse were described. The 2-year cumulative incidence (CI) of SCNS relapse was 2.7 %. A total of 729, 1024, and 281 patients were classified as low-, intermediate-, and high-risk CNS international prognostic index (CNS-IPI) with corresponding 2-year CI of SCNS relapse of 1.5, 3.1, and 4.6 %, respectively (p < 0.001). Univariate analysis demonstrated advance stage disease, poor performance status, elevated lactate dehydrogenase, presence of B symptoms, more than one extranodal organ involvement, high IPI, and high CNS-IPI group as predictive factors for SCNS relapse. Rituximab exposure and intrathecal chemoprophylaxis offered no protective effect against SCNS relapse. At the time of analysis, six patients were alive. Median OS in SCNS relapsed patients was significantly shorter than relapsed patients without CNS involvement (13.2 vs 22.6 months) (p < 0.001). Primary causes of death were progressive disease (n = 35, 63.6 %) and infection (n = 9, 16.7 %). In conclusion, although the incidence of SCNS relapse in our cohort was low, the prognosis was dismal. Prophylaxis for SCNS involvement was underused even in high-risk patients. Novel approaches for SCNS relapse prophylaxis and managements are warranted.

Hypercoagulable state as demonstrated by thromboelastometry in hemoglobin E/beta-thalassemia patients: Association with clinical severity and splenectomy status.

INTRODUCTION: Patients with hemoglobin E/beta-thalassemia disease (E/ß) are at risk of thromboembolism. Rotational thromboelastometry (ROTEM®) can be used to determine a hypercoagulable state. The objective was to describe the hemostatic and thromboelastometric changes in pediatric patients with E/ß with different clinical severity, in comparison with healthy children as controls. MATERIALS AND METHODS: Fifty-three pediatric patients with E/ß and 21 healthy children were enrolled. The clinical severity of E/ß was categorized by using the clinical severity scores. All subjects were tested for complete blood count, protein C activity (PC), total protein S (PS), antithrombin (AT), D-dimer and fibrinogen (Fib) levels and thromboelastometry, measured by ROTEM®. RESULTS: The levels of PC (65.7 vs 118.5%), PS (46.8 vs 78.4%), AT (95.7 vs 105.7%) and Fib (217 vs 294 mg/dL) were significantly lower, and the platelet count (PLT) was significantly higher in the patient group than the controls. The maximum clot firmness (MCF) of patients with moderate disease who were previously splenectomized (seven patients) and patients with severe disease (nine patients) were higher than patients who had intact spleen with moderate disease, patients with mild disease and controls (P<0.05). Only PLT had significant correlation with MCF (P<0.05). CONCLUSIONS: Hypercoagulable state was demonstrated by ROTEM® in patients with E/ß with severe disease and who were previously splenectomized. The hypercoagulable state was associated with the higher numbers of PLT rather than the decrease of PC, PS, and AT.

Rituximab maintenance for patients with aggressive B-cell lymphoma in first remission: results of the randomized NHL13 trial.

We investigated rituximab maintenance therapy in patients with diffuse large B-cell lymphoma (n=662) or follicular lymphoma grade 3b (n=21) in first complete remission. Patients were randomized to rituximab maintenance (n=338) or observation (n=345). At a median follow-up of 45 months, the event-free survival rate (the primary endpoint) at 3 years was 80.1% for rituximab maintenance versus 76.5% for observation. This difference was not statistically significant for the intent-to-treat population (likelihood ratio P=0.0670). The hazard ratio by treatment arm was 0.79 (95% confidence interval 0.57-1.08; P=0.1433). The secondary endpoint, progression-free survival was also not met for the whole statistical model (likelihood ratio P=0.3646). Of note, rituximab maintenance was superior to observation when treatment arms only were compared (hazard ratio: 0.62; 95% confidence interval 0.43-0.90; P=0.0120). Overall survival remained unchanged (92.0 versus 90.3%). In subgroup analysis male patients benefited from rituximab maintenance with regards to both event-free survival (84.1% versus 74.4%) (hazard ratio: 0.58; 95% confidence interval 0.36-0.94; P=0.0267) and progression-free survival (89.0% versus 77.6%) (hazard ratio: 0.45; 95% confidence interval 0.25-0.79; P=0.0058). Women had more grade 3/4 adverse events (P=0.0297) and infections (P=0.0341). Men with a low International Prognostic Index treated with rituximab had the best outcome. In summary, rituximab maintenance in first remission after R-CHOP-like treatment did not prolong event-free, progression-free or overall survival of patients with aggressive B-non-Hodgkin lymphoma. The significantly better outcome of men warrants further studies prior to the routine use of rituximab maintenance in men with low International Prognostic Index. This trial is registered under EUDRACT #2005-005187-90 and www.clinicaltrials.gov as #NCT00400478.

Effect of acetylsalicylic acid on thalassemia with pulmonary arterial hypertension.

OBJECTIVE: To compare pulmonary artery systolic pressure (PASP) between thalassemic patients with pulmonary arterial hypertension (PAH) for whom acetylsalicylic acid (ASA) was and was not prescribed after 1 year. METHODS: A retrospective cohort study was conducted at the hematological outpatient clinic at Chiang Rai Hospital, Chiang Rai, Thailand. All new cases of thalassemia with PAH from January 2007 to January 2012 were studied at the first month and at 12 months. The patients were classified into two groups. In one group, ASA 81 mg daily was prescribed for 1 year, whereas in another group no ASA was prescribed, due to its contraindications, which included bleeding, gastrointestinal side effects, and thrombocytopenia. PASP, estimated by a Doppler echocardiography, was measured by the same cardiologist. Propensity score adjustment was used to control confounding variables by indication and contraindication. Multivariable regression analysis was used to evaluate the effects of ASA. RESULTS: Of the 63 thalassemia patients with PAH, there were 47 (74.6%) in the ASA group and 16 (25.4%) in the no ASA group. ASA, as compared with no ASA, did not significantly reduce PASP (adjusted difference -0.95; 95% confidence interval -16.99 to 15.10; P=0.906). CONCLUSION: Low-dose ASA may not have a beneficial effect on PASP after 1 year of treatment of PAH in thalassemia.

Benefits of chronic blood transfusion in hemoglobin E/ß thalassemia with pulmonary arterial hypertension.

OBJECTIVE: The aim of the research reported here was to compare pulmonary artery systolic pressure (PASP) and 6-minute walk distance after 1 year of follow-up in hemoglobin E/ß thalassemia (E/ß-Thal) with pulmonary arterial hypertension (PAH) patients who received chronic blood transfusions versus those who received occasional transfusions. METHODS: A nonrandomized clinical trial was conducted at the Hematological Outpatient Clinic of Chiang Rai Hospital, Thailand. All adult cases of E/ß-Thal with PAH (defined as PASP >35 mmHg by Doppler echocardiography) were evaluated and followed for the next 12 months. The patients were classified into two groups by patient preference. Group 1 patients received chronic blood transfusions - one to two units of leukocyte-poor packed red cells every 2-4 weeks - over 1 year to maintain pre-transfusion hemoglobin levels of ≥7.0 g/dL. Group 2 patients received occasional transfusions over the course of 1 year, with more than 4 weeks between transfusions. All patients were treated with iron chelation when serum ferritin levels were ≥1,000 µg/dL. PASP and the 6-minute walk distance were evaluated at baseline and at 6 and 12 months. Propensity score adjustment was used to control for confounding by indication and contraindication. Multivariable regression analysis was used to evaluate the effects of chronic blood transfusion. RESULTS: There were 16 (53.3%) patients in Group 1 and 14 (46.7%) in Group 2. At 12 months, patients in Group 1 had a greater reduction in PASP than those in Group 1 (adjusted mean difference, -16.83; 95% confidence interval, -26.35 to -7.32; P=0.001). The 6-minute walk distance at 12 months in Group 1 patients was greater than that in Group 2 patients (adjusted mean difference, 46.55; 95% confidence interval, 18.08 to 75.02; P=0.001). CONCLUSION: This study found evidence that chronic blood transfusions may have beneficial effects in PAH in thalassemia patients over 1 year.

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.

Management of multiple myeloma in Asia: resource-stratified guidelines.

Treatment of multiple myeloma has undergone substantial developments in the past 10 years. The introduction of novel drugs has changed the treatment of the disease and substantially improved survival outcomes. Clinical practice guidelines based on evidence have been developed to provide recommendations on standard treatment approaches. However, the guidelines do not take into account resource limitations encountered by developing countries. The huge disparities in economy, health-care infrastructure, and access to novel drugs in Asian countries hinder the delivery of optimum care to every patient with multiple myeloma in Asia. In this Review we outline the guidelines that correspond with different levels of health-care resources and expertise, with the aim to unify diagnostic and therapeutic guidelines and help with the design of future studies in Asia.

Inferior progression-free survival for Thai patients with diffuse large B-cell lymphoma treated under Universal Coverage Scheme: the impact of rituximab inaccessability.

The impact of health insurance with inequitable rituximab coverage on the survival of patients with diffuse large B-cell lymphoma (DLBCL) has never been reported. We conducted a nationwide multicenter analysis on the outcome of 553 adult patients consecutively diagnosed with DLBCL between July 2003 and June 2006, in whom treatment cost was reimbursed under the Civil Servant Medical Benefit Scheme (CSMBS) (n =201) or the Universal Coverage Scheme (UCS) (n =352). The international prognostic index was comparable between the two payment groups. Rituximab-based therapy was administered in 45.3% and 3.1% of CSMBS and UCS patients, respectively (p <0.001). With a median follow-up of 24.6 months, the 6-year progression-free survival (PFS) was superior for CSMBS patients (34.2 vs. 23.2%, p =0.005). "Not treated with rituximab-based therapy" was the strongest adverse prognostic feature indicating a short PFS (hazard ratio 2.1, p <0.001). It is concluded that lack of access to rituximab is the principal factor accounting for the inferior PFS observed in Thai patients with DLBCL who are treated under the UCS.

CHOEP-21 chemotherapy for newly diagnosed nodal peripheral T-cell lymphomas (PTCLs) in Maharaj Nakorn Chiang Mai Hospital.

OBJECTIVE: To determine the effectiveness and tolerability of the combination of chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) with the addition of etoposide (CHOEP-21) for newly diagnosed nodal peripheral T-cell lymphomas (PTCLs). MATERIAL AND METHOD: Between January 2009 and October 2011, patients aged 18 to 60 years with newly diagnosed nodal PTCLs at the Maharaj Nakorn Chiang Mai Hospital were enrolled to receive CHOEP-21 every three weeks for eight cycles. G-CSF prophylaxis was given to all patients. RESULTS: Twenty-four patients were enrolled. Twenty of them were male with a median age of 49 years. The majority of patients (66.7%) had PTCL, not otherwise specified (PTCL, NOS), and 95.8% of the patients were in stage III or IV. The overall response rate was 58% with 42% having complete response. The response rates were better among patients with ALK-negative anaplastic large cell lymphoma (ALCL; 100%) and angioimmunoblastic T-cell lymphoma (AITL; 85%) than those with PTCL, NOS (44%). With a median follow-up of 21 months, the patients had an estimated 2-year event-free survival, and an overall survival rate of 37.6% and 54.4%, respectively. The most common adverse effects were infection and hematologic toxicities that was manageable. CONCLUSION: Although CHOEP-21 induced favorable responses in patients with ALK-negative ALCL and AITL, the responses were not durable and further therapy is mandated in management of patients with nodal PTCL.

Clinical indicators for pulmonary arterial hypertension in thalassemia.

OBJECTIVE: To explore clinical indicators for pulmonary arterial hypertension (PAH) in thalassemia (Thal). MATERIAL AND METHOD: A study was conducted in thalassemia patients at Chiang Rai Hospital, Chiang Rai, Thailand. Pulmonary artery systolic pressure (PASP) was determined by doppler echocardiography and PAH was defined as PASP > 35 mmHg. Patient characteristics were extracted from medical records. Characteristics of patients with and without PAH were compared. Risk indicators were explored with logistic regression analysis. RESULTS: Two hundred twenty four patients were included, 144 E/beta-Thal, 37 homozygous beta-Thal and 43 Hb H disease. There were 65 patients (29.0%) with PAH, 53 (81.5%) with E/beta-Thal, 8 (12.3%) with homozygous beta-Thal and 4 (6.2%) with Hb H disease. In a multivariable analysis, features significantly associated with PAH were E/beta-Thal (OR = 1.98, 95% CI; 1.29-3.01) and post splenectomy status (OR = 2.36, 95% CI; 1.17-4.73). CONCLUSION: Significant indicators for PAH in thalassemia were E/beta-Thal and post splenectomy status.

Modification of solid phase red cell adherence assay for the detection of platelet antibodies in patients with thrombocytopenia.

Platelet refractoriness is caused by HLA antibodies and platelet-specific antibodies. Current methods used to detect antiplatelet antibodies have limitations. Solid phase red cell adherence (SPRCA) lacks sensitivity and requires a second assay using chloroquine-treated intact platelets to specify the response due to anti-HLA. We modified SPRCA by using 2 types of antihuman platelet antibodies with different specificities toward platelet lysate and tested samples from 361 patients (69 with unexplained thrombocytopenia and 292 with poor response to platelet transfusions not explicable by alloimmunization or the clinical situation) and 50 from healthy volunteers. Our method compared favorably with platelet suspension direct immunofluorescence. All samples from healthy volunteers were negative; of the samples from the patient population, 240 were positive (147 samples had only antiplatelet and 3 samples had only anti-HLA antibodies). This modified technique had a sensitivity of 98% and a specificity of 91%.

National survey of patients with hemophilia and other congenital bleeding disorders in Thailand.

A national survey of patients with hemophilia and other congenital bleeding disorders in Thailand was conducted in the years 2000 to 2002. Questionnaires were sent to physicians working at hospitals throughout the country. Although the overall response rate to the questionnaires was 19%, the two highest rates of 80% and 73.7% were found at university and regional hospitals, respectively, where most of the patients received their diagnosis and treatment. A total of 1,450 patients comprised of hemophilia 1,325 cases, von Willebrand disease, 69 cases, congenital factor VII deficiency, 15 cases, hereditary platelet dysfunction, 22 cases, and undefined causes of congenital bleeding disorders, 19 cases. Most were pediatric patients <15 years of age. Treatment was mainly given on demand for a bleeding episode, while only 8.6% received additional home treatment for early bleeding episodes. Replacement therapy primarily relied on fresh frozen plasma, cryoprecipitate and cryo-removed plasma. Factor concentrate was seldom used because of the high price. As a result, hemophilia care services in Thailand should be strengthened by providing comprehensive education for medical personnel, making available simple laboratory kits to determine hemophilia A and B, ensuring an adequate supply of blood components and affordable factor concentrate, and establishing home care treatment.