Maximum standardized uptake value (SUVmax) and maximum tumor diameter (MTD) have been shown to reflect survival outcome in diffuse large B cell lymphoma (DLBCL). However, applying these values to primary extranodal DLBCL is difficult because they are separate nosological entities with differences in genetic origin. We therefore decided to evaluate whether SUVmax and MTD on 2-[fluorine-18]-fluoro-2-deoxy-D-glucose (18-FDG) positron emission tomography (PET) would affect the survival outcome in primary extranodal DLBCL.
From October 2005 to November 2010, 76 primary extranodal DLBCL patients receiving R-CHOP therapy were analyzed. All patients had undergone an initial 18-FDG PET/CT and conventional computed tomography (CT) of the neck, chest, abdomen, and pelvis for staging. Median follow-up period was 35 months.
The SUVmax and MTD cut-off values were 11.0 and 7.5 cm, respectively. SUVmax≥11.0 predicted a short progression free survival (PFS, P=0.002) and overall survival (OS, P=0.002). MTD≥7.5 cm was associated with poor PFS (P=0.003) and OS (P=0.003). High International Prognostic Index (IPI) was also associated with the survival outcome (PFS, P=0.046; OS, P=0.030). Multivariate analysis revealed that SUVmax≥11.0 (PFS, hazard ratio [HR]=10.813, P=0.024; OS, HR=6.312, P=0.015); MTD≥7.5 cm (PFS, HR=5.631, P=0.008; OS, HR=4.072, P=0.008); and high IPI (PFS, P=0.027; OS, P=0.046) were independent prognostic factors.
It appears that both MTD and SUVmax can be independent prognostic factors in primary extranodal DLBCL.
Lymphoma; Large B-cell; Extranodal
Autologous stem cell transplantation (ASCT) has become the treatment of choice for patients with multiple myeloma (MM). Studies have shown that maintenance treatment with interferon-alpha is associated with improved survival rates following ASCT. However, despite these recent advances in regimes, relapses are inevitable; thus, the prediction of relapse following ASCT requires assessment.
We retrospectively analyzed 39 patients who received ASCT between 2003 and 2008. All patients received chemotherapy with vincristine, adriamycin, and dexamethasone (VAD), and ASCT was performed following high-dose melphalan conditioning therapy. We evaluated the influence of the post-transplant day +14 (D+14) bone marrow plasma cell percent (BMPCp) (≥ 2 vs. < 2%), international scoring system (ISS) stage (II vs. III), response after 3 cycles of VAD therapy (complete response [CR] vs. non-CR), deletion of chromosome 13q (del[13q]) (presence of the abnormality vs. absence), and BMPCp at diagnosis (≥ 50 vs. < 50%) on progression-free survival (PFS) and overall survival (OS).
During the median follow-up of 28.0 months, the median PFS and OS were 29.1 and 42.1 months, respectively. By univariate analysis, ISS stage III at diagnosis, BMPCp ≥ 50% at diagnosis, CR after 3 cycles of VAD therapy, del (13q) by fluorescence in situ hybridization, and BMPCp ≥ 2% at post-transplant D+14 were correlated with PFS and OS. A multivariate analysis revealed that a post-transplant D+14 BMPCp ≥ 2% (PFS, hazard ratio [HR] = 4.426, p = 0.008; OS, HR = 3.545, p = 0.038) and CR after 3 cycles of VAD therapy (PFS, HR = 0.072, p = 0.014; OS, HR = 0.055, p = 0.015) were independent prognostic parameters.
Post-transplant D+14 BMPCp is a useful parameter for predicting the outcome for patients with MM receiving ASCT.
Multiple myeloma; Stem cell transplantation; Bone marrow; Plasma cell
Serum ferritin is a marker of acute phase reactions and iron storage. In addition, hematologic malignancies are associated with elevated serum ferritin levels. Other studies have suggested that ferritin is a surrogate for advanced disease and has an impact on relapse, because elevated serum ferritin predicts overall survival (OS) and relapse-free survival following autologous stem cell transplantation for lymphomas.
We studied 89 consecutive patients with newly diagnosed multiple myeloma to determine the value of serum ferritin in comparison with known prognostic factors.
The OS in the elevated serum ferritin group (≥300 ng/mL) was shorter than that in the normal serum ferritin group (<300 ng/mL, p<0.001) after a median follow-up of 25 months. In univariate analysis, elevated ferritin was correlated with poor survival in the patients (relative risk [RR], 2.588; 95% confidence interval [CI], 1.536 to 4.358; p<0.001). Furthermore, multivariate analysis showed that elevated serum ferritin was an independent predictor of mortality in patients with multiple myeloma (RR, 2.594; 95% CI, 1.403 to 4.797; p=0.002).
The serum ferritin can a prognostic parameter of survival as well as disease activity in patients with multiple myeloma.
Ferritin; Multiple myeloma; Survival
Previous reports have suggested that a high serum cyclosporine A (CsA) level could result in a lower incidence of acute-graft-versus-host disease (aGVHD). An elevated serum lactate dehydrogenase (LDH) level has been reported to be an adverse predictor of outcome in stem cell transplantation (SCT) for acute myeloid leukemia. In this study, we retrospectively analyzed the records of 24 patients who received allogeneic SCT from an HLA-matched sibling donor for acute and chronic myelogenous leukemia. Univariate analysis showed that two factors (the serum CsA level at the third week after SCT and the LDH level at the third week after SCT) were significantly associated with the incidence of aGVHD among several variables (age, sex, stem cell source, cell dose, C-reactive protein, absolute lymphocyte count, conditioning regimens, and time to engraftment). A higher serum level of CsA and lower serum LDH level at the third week after SCT were associated with a lower incidence of aGVHD (P=0.015, 0.030). In multivariate analysis, the serum CsA level (hazard ratio [HR], 0.12; 95% confidence interval [CI], 0.022-0.652, P=0.0014) and serum LDH level (HR, 6.59; 95% CI, 1.197-36.316, P=0.030) at the third week after SCT were found to be independent factors that were significantly associated with the development of aGVHD. We conclude that a high CsA level and low LDH level might predict a low cumulative incidence of aGVHD after allogeneic transplantation from a matched sibling donor.
Leukemia, Myeloid, Acute; Cyclosporine; Graft vs Host Disease
We initiated this study to investigate whether combining Helicobacter pylori eradication with immunosuppressive therapy provides an additional benefit to patients with idiopathic thrombocytopenic purpura (ITP) that has relapsed or has not responded to steroid and/or danazol therapy in patients who have H. pylori infection. Thirty-four patients with chronic ITP that had relapsed or failed to steroid and/or danazol therapy were assessed for H. pylori infection. Of the 21 confirmed cases, 12 patients were given H. pylori eradication therapy alone (EA), while 9 patients received eradication therapy combined with immunosuppressive therapy (EI). The response rate was not significantly different between patients in the EA and those in the EI group (41.7% in the EA group vs. 66.7% in the EI group, p=0.345). The median platelet count at 6 months after therapy was higher in the EI group patients (75×109/L in the EI group patients vs. 18×109/L in the EA group patients, p=0.028). The median response duration was also longer in the EI group patients (9 months in the EI group patients vs. 3 months in the EA group patients, p=0.049). These results show that a significant benefit is gained by the use of H. pylori eradication combined with immunosuppressive therapy over the use of eradication therapy alone for patients with chronic ITP.
Helicobacter pylori; Purpura, Thrombocytopenic, Idiopathic; Eradication
A retrospective study was conducted to determine the mortality, causes and risk factors for death among HIV-infected patients receiving antiretroviral therapy (ART) in Korea. The outcomes were determined by time periods, during the first year of ART and during 1-5 yr after ART initiation, respectively. Patients lost to follow-up were traced to ascertain survival status. Among 327 patients initiating ART during 1998-2006, 68 patients (20.8%) died during 5-yr follow-up periods. Mortality rate per 100 person-years was 8.69 (95% confidence interval, 5.68-12.73) during the first year of ART, which was higher than 4.13 (95% confidence interval, 2.98-5.59) during 1-5 yr after ART. Tuberculosis was the most common cause of death in both periods (30.8% within the first year of ART and 16.7% during 1-5 yr after ART). During the first year of ART, clinical category B and C at ART initiation, and underlying malignancy were significant risk factors for mortality. Between 1 and 5 yr after ART initiation, CD4 cell count ≤ 50 cells/µL at ART initiation, hepatitis B virus co-infection, and visit constancy ≤ 50% were significant risk factors for death. This suggests that different strategies to reduce mortality according to the time period after ART initiation are needed.
HIV; Antiretroviral Therapy; Mortality; Cause of Death; Risk Factors; Loss to Follow-up; Retention in Care; Visit Constancy
Although a decrease in acquired immunodeficiency syndrome (AIDS)-related mortality has been documented in highly active antiretroviral therapy (HAART) era, there are no published data comparing specific causes of death between pre-HAART and HAART era in Korea. Mortality and cause of death were analyzed in three treatment periods; pre-HAART (1990-1997), early-HAART (1998-2001), and late-HAART period (2002-2011). The patients were retrospectively classified according to the treatment period in which they were recruited. Although mortality rate per 100 person-year declined from 8.7 in pre-HAART to 4.9 in late-HAART period, the proportion of deaths within 3 months of initial visit to study hospital significantly increased from 15.9% in pre-HAART to 55.1% in late-HAART period (P < 0.001). Overall, 59% of deaths were attributable to AIDS-related conditions, and Pneumocystis pneumonia (PCP) was the most common cause of death (20.3%). The proportion of PCP as cause of death significantly increased from 8.7% in pre-HAART to 31.8% in late-HAART period (P < 0.001). Despite of significant improvement of survival, there was still a high risk of early death in patients presenting in HAART era, mainly due to late human immunodeficiency virus (HIV) diagnosis and late presentation to care.
HIV; Antiretroviral Therapy; Mortality; Cause of Death
The objective of this study was to investigate whether metabolic tumor volume (MTV) by positron emission tomography (PET) can be a potential prognostic tool when compared with Ann Arbor stage, in stages II and III nodal diffuse large B cell lymphoma (DLBCL). We evaluated 169 patients with nodal stages II and III DLBCL who underwent measurements with PET prior to rituximab combined with cyclophosphamide, adriamycin, vincristine, and prednisone (R-CHOP). Cutoff point of MTV was measured using the receiver operating characteristic (ROC) curve. During a median period of 36 months, stage II was 59.2% and III was 40.8%. Using the ROC curve, the MTV of 220 cm3 was the cutoff value. The low MTV group (<220 cm3) had longer progression-free survival (PFS) and overall survival (OS), compared with the high MTV group (≥220 cm3) (p < 0.001, p < 0.001). Stage II patients had longer survival than those in stage III (PFS, p = 0.011; OS, p = 0.001). The high MTV group had lower PFS and OS patterns, regardless of stage, compared with the low MTV group (p < 0.001, p < 0.001). Multivariate analysis revealed an association of the high MTV group with lower PFS and OS (PFS, hazard ratio (HR) = 5.300, p < 0.001; OS, HR = 7.009, p < 0.001), but not stage III (PFS, p = 0.187; OS, p = 0.054). Assessment of MTV by PET had more potential predictive power than Ann Arbor stage in the patients that received R-CHOP.
Diffuse large B cell lymphoma; Positron emission tomography; Rituximab
Cytogenetic abnormalities (CAs) have been reported frequently in patients with otherwise typical aplastic anemia (AA), but their implications in the prognosis and in the evolution to hematologic malignancies are controversial.
We retrospectively analyzed 127 adult AA patients who had successful cytogenetic analysis at initial diagnosis.
The patients were classified into 3 groups according to the initial and follow-up results of cytogenetic profiles. Group 1 included patients who had persistent AA with normal cytogenetic profiles (N=117); Group 2, those who had a normal cytogenetic profile at initial diagnosis but later acquired CA (N=4, 3.1%); and Group 3, those who had CA at the initial diagnosis, regardless of follow-up cytogenetic status (N=6,4.7%). In Group 2, 2 patients later developed CA without progression to acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS); the other 2 patients later progressed to AML. None of the patients in Group 3 progressed to AML or MDS. There was no significant difference in overall survival between Groups 1 and 3.
AA patients with CA at initial diagnosis or follow-up may not be at greater risk for evolution to AML or MDS, or show shorter survival periods. Prospective studies and a larger patient samples are needed to establish the clinical relevance of CA.
Aplastic anemia; Cytogenetic abnormality
Bortezomib has significant activity in treating multiple myeloma (MM). The risk of herpes zoster (HZ) has been reported to increase significantly with bortezomib treatment, but the predisposing factors for HZ are not clear. This study is a retrospective analysis of the relevant risk factors for HZ in Korean MM patients treated with bortezomib.
Sixty-six patients with refractory or relapsed MM who underwent chemotherapy with bortezomib were included in the study. Prophylactic antiviral drugs were not used for treatment. The following parameters were reviewed: age, gender, stage and type of MM, extent of previous treatment, history of HZ, duration from the time of diagnosis to the time of bortezomib treatment initiation, and absolute lymphocyte counts (ALC) at the time of bortezomib treatment initiation.
The incidence of HZ was 16.7%. There were no intergroup differences between the HZ-positive and the HZ-negative groups with regard to a history of HZ, number of previous treatments, and exposure to steroids before bortezomib treatment. The median duration from the time of MM diagnosis to the time of bortezomib treatment initiation in the HZ-positive group was significantly shorter than that in the HZ-negative group. The median ALC at the time of bortezomib initiation in the HZ-positive group was significantly lower than that in the HZ-negative group.
Bortezomib itself might act as a risk factor for HZ by inhibiting cell-mediated immunity, and patients with low ALC at the time of bortezomib treatment initiation were at greater risk of HZ during bortezomib treatment.
Multiple myeloma; Protease inhibitors; Herpes zoster
A refractory and resistant disease to conventional induction chemotherapy and relapsed disease are considered as the most important adverse prognostic factors for acute myeloid leukemia (AML). Sixty-one patients (median age, 33.6 yr) with relapsed or refractory AML were treated with the FLAG regimen that consisted of fludarabine (30 mg/m2, days 1-5), cytarabine (2.0 g/m2, days 1-5) and granulocyte colony-stimulating factor. Of the treated patients 29 patients (47.5%) achieved complete remission (CR). Higher CR rates were observed for patients with a first or second relapse as compared to patients with a primary refractory response or relapse after stem cell transplantation (HSCT). There was a significant difference in the response rates according to the duration of leukemia-free survival (pre-LFS) before chemotherapy (P=0.05). The recovery time of both neutrophils (≥500/µL) and platelets (≥20,000/µL) required a median of 21 and 18 days, respectively. Treatment-related mortality (TRM) occurred in seven patients (11.4%), of which 71.4% of TRM was caused by an invasive aspergillosis infection. After achieving CR, 18 patients underwent consolidation chemotherapy and six patients underwent allogeneic HSCT. In conclusion, FLAG chemotherapy without idarubicin is a relatively effective and well-tolerated regimen for relapsed or refractory AML and the use of FLAG chemotherapy has allowed intensive post-remission therapy including HSCT.
Leukemia, Myeloid, Acute; FLAG Chemotherapy; Toxicity
To date, an effective salvage chemotherapy regimen for the treatment of refractory or relapsing non-Hodgkin's lymphoma (NHL) has not been discovered. This study was conducted to evaluate the efficacy and safety of gemcitabine, etoposide, cisplatin, and dexamethasone in relapsed or refractory NHL patients.
All patients had histologically proven relapsed or refractory NHL. Treatments consisted of gemcitabine 700 mg/m2 by continuous i.v. on days 1 and 8; etoposide 40 mg/m2 by i.v. on days 1-4; cisplatin 60 mg/m2 by i.v. on day 1; or dexamethasone 40 mg by i.v. on days 1-4 (GEPD) every 21 days. The primary end point was the patient response rate following two cycles of treatment. After two cycles, stem cells were harvested using mobilizing regimens (ESHAP or GEPD plus filgrastim), and this was followed by autologous stem cell transplantation or four additional cycles of GEPD.
Between January 2005 and January 2006, 20 patients (13 males and 7 females) were enrolled in the study. The median age was 53 (range 16-75) years. The most common histology was diffuse large B-cell lymphoma (n=10). The median follow-up duration was 5.2 (range 1.0-16.0) months. After two cycles, the overall response rate was 50.0% (10/20), including two complete responses and eight partial responses. The dose-limiting toxicity was myelosuppression. Grade IV neutropenia and thrombocytopenia occurred in 13 (65.0%) and 6 patients (30.0%), respectively. The median number of CD34-positive cells collected was 6.0 (range, 2.8-11.6) ×106/kg. Of the 17 patients < 66 years of age, 4 (23.5%) proceeded to autologous stem cell transplantation.
GEPD chemotherapy in patients with refractory or relapsed NHL was effective as a salvage therapy and helpful for stem cell harvest followed by autologous transplantation.
Non-Hodgkin's lymphoma; Refractory or relapsed; Gemcitabine
The objective of the current study was to investigate the treatment outcomes for the use of cyclophosphamide, adriamycin, vincristine, and prednisolone (CHOP) chemotherapy in adult patients with hemophagocytic lymphohistiocytosis (HLH). Seventeen HLH patients older than 18 yr of age were treated with CHOP chemotherapy. A response evaluation was conducted for every two cycles of chemotherapy. With CHOP chemotherapy, complete response was achieved for 7/17 patients (41.2%), a partial response for 3/17 patients (17.6%), and the overall response rate was 58.8%. The median response duration (RD) was not reached and the 2-yr RD rate was 68.6%, with a median follow-up of 100 weeks. Median overall survival (OS) was 18 weeks (95% CI, 6-30 weeks) and the 2-yr OS rate was 43.9%. Reported grade 3 or 4 non-hematological toxicities were increased serum liver enzyme levels and stomatitis. Grade 3 or 4 hematological toxicities were leukopenia (50.8%), anemia (20%), and thrombocytopenia (33.9%). Neutropenic fever was observed in 21.6% of patients (14/65 cycles), and most of the cases were resolved with supportive care including treatment with broad-spectrum antibiotics. CHOP chemotherapy seems to be effective in adult HLH patients and the toxicities are manageable.
Lymphohistiocytosis, Hemophagocytic; Herpesvirus 4, Human; Lymphoma; CHOP Protocol
We report a case of two consecutive episodes of acute hemolytic transfusion reactions (HTRs) due to multiple alloantibodies in a 34-yr-old man who suffered from avascular necrosis of left femoral head. He received five units of packed red blood cells (RBCs) during surgery. Then the transfusion of packed RBCs was required nine days after the surgery because of the unexplained drop in hemoglobin level. The transfusion of the first two units resulted in fever and brown-colored urine, but he received the transfusion of another packed RBCs the next day. He experienced even more severe symptoms during the transfusion of the first unit. We performed antibody screening test, and it showed positive results. Multiple alloantibodies including anti-E, anti-c and anti-Jkb were detected by antibody identification study. Acute HTRs due to multiple alloantibodies were diagnosed, and the supportive cares were done for 6 days. We suggest the antibody screening test should be included in the panel of pretransfusion tests for safer transfusion, and it is particularly mandatory for the patients with multiple transfusions, pregnant women, and preoperative patients.
Novel agents to treat multiple myeloma (MM) have increased complete respone (CR) rates compared with conventional chemotherapy, and the quality of the response to treatment has been correlated with survival. The purpose of our study was to show how of early response to bortezomib combined chemotherapy influences survival in patients with newly diagnosed MM who are ineligible for stem cell transplantation. We assessed patient responses to at least four cycles of bortezomib using the International Myeloma Working Group response criteria. The endpoints were comparisons of progression free survival (PFS) and overall survival (OS) between early good response group (A group) and poor response group (B group). We retrospectively analyzed data from 129 patients registered by the Korean Multiple Myeloma Working Party, a nationwide registration of MM patients. The 3 yr PFS for the A and B groups was 55.6% and 18.4%, respectively (P < 0.001). The 3 yr OS for the A and B groups was 65.3% and 52.9%, respectively (P = 0.078). The early response to at least four cycle of bortezomib before next chemotherapy may help predict PFS in patients with MM who are ineligible stem cell transplantation.
Early Response; Multiple Myeloma; Bortezomib; Survival
To evaluate efficacy in patients with brain metastasis (BM) on entry into the lapatinib expanded access program (LEAP).
LEAP is a worldwide, single-arm, open-label study. HER2-positive, locally-advanced or metastatic breast cancer patients with progression after an anthracycline, taxane, and trastuzumab were eligible. Patients received capecitabine 2000 mg/m2 daily in two divided doses, days 1–14, every 21 days and lapatinib 1250 mg once daily.
Among 186 patients enrolled in 6 Korean centers, 58 had BM. Progression-free survival (PFS) was 18.7 weeks in patients with BM and 19.4 weeks without BM (P = 0.88). In patients with BM, brain response was synchronized with systemic responses (P = 0.0001). Overall survival (OS) was 48.9 weeks in patients with BM and 64.6 weeks without BM (P = 0.23). Multivariable analysis found hormone receptor positivity (P = 0.003) and clinical benefit rate (CBR) of combined systemic and brain disease (P < 0.0001) significantly associated with prolonged brain PFS, and CBR of combined systemic and brain disease (P = 0.03) and longer trastuzumab use (P = 0.047) associated with prolonged OS in patients with BM; prior capecitabine did not affect PFS or OS in patients with BM.
Lapatinib plus capecitabine is equally effective in patients with or without BM.
Brain Metastasis; HER2-positive Metastatic Breast Cancer; Lapatinib and Capecitabine Therapy; LEAP
Heptaplatin (Sunpla) is a cisplatin derivative. A phase IIb trial using heptaplatin resulted in a 34% response rate with mild nephrotoxicity. We conducted a randomized phase III trial of heptaplatin plus 5-FU compared with cisplatin plus 5-FU in patients with advanced gastric cancer.
Materials and Methods
One hundred seventy-four patients (heptaplatin, n=88; cisplatin, n=86) from 13 centers were enrolled. The eligibility criteria were as follows: patients with pathologically-proven adenocarcinoma, chemonaive patients, or patients who had received only single adjuvant chemotherapy, and who had a measurable or evaluable lesion. On day 1, heptaplatin (400 mg/m2) or cisplatin (60 mg/m2) was given over 1 hour with 5-FU (1 gm/m2) on days 1~5 every 4 weeks.
At the time of survival analysis, the median overall survival was 7.3 months in the 5-FU + heptaplatin (FH) arm and 7.9 months in the 5-FU + cisplatin (FP) arm (p=0.24). Of the FH patients, 34.2% (complete response [CR], 1.3%; partial response [PR], 32.9%) experienced a confirmed objective response compared with 35.9% (CR 0%, PR 35.9%) of FP patients (p=0.78). The median-time-to-progression was 2.5 months in the FH arm and 2.3 months in the FP arm. The incidence of neutropenia was higher with FP (28%) than with FH (16%; p=0.06); grade 3~4 nausea and vomiting were more frequent in the FP than in the FH arm (p=0.01 and p=0.05, respectively). The incidence of increased proteinuria and creatininemia was higher with FH than with FP; however, there was no statistical difference. There were no treatment-related deaths.
Heptaplatin showed similar effects to cisplatin when combined with 5-FU in advanced gastric cancer patients with tolerable toxicities.
Combination chemotherapy; Advanced gastric cancer; Heptaplatin