Long-term outcomes and central nervous system relapse in extranodal natural killer/T-cell lymphoma.

To elucidate the long-term outcomes of non-anthracycline-containing therapies and central nervous system (CNS) events in patients with extranodal NK/T-cell lymphoma, nasal type (ENKTL), the clinical data of 313 patients with ENKTL diagnosed between 2000 and 2013 in a nationwide retrospective study in Japan were updated and analyzed. At a median follow-up of 8.4 years, the 5-year overall survival (OS) and progression-free survival (PFS) were 71% and 64%, respectively, in 140 localized ENKTL patients who received radiotherapy-dexamethasone, etoposide, ifosfamide, and carboplatin (RT-DeVIC) in clinical practice. Nine (6.4%) patients experienced second malignancies. In 155 localized ENKTL patients treated with RT-DeVIC, 10 (6.5%) experienced CNS relapse (median, 12.8 months after diagnosis). In five of them, the events were confined to the CNS. Nine of the 10 patients who experienced CNS relapse died within 1 year after CNS relapse. Multivariate analysis identified gingival (hazard ratio [HR], 54.35; 95% confidence interval [CI], 8.60-343.35) and paranasal involvement (HR, 7.42; 95% CI, 1.78-30.89) as independent risk factors for CNS relapse. In 80 advanced ENKTL patients, 18 received steroid (dexamethasone), methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) chemotherapy as first-line treatment. Patients who received SMILE as their first-line treatment tended to have better OS than those who did not (p = 0.071). Six (7.5%) advanced ENKTL patients experienced isolated CNS relapse (median, 2.6 months after diagnosis) and died within 4 months of relapse. No second malignancies were documented in advanced ENKTL patients. In the entire cohort, the median OS after first relapse or progression was 4.6 months. 12 patients who survived 5 years after PFS events were disease-free at the last follow-up. Of those, 11 (92%) underwent hematopoietic stem cell transplantation. Our 8-year follow-up revealed the long-term efficacy and safety of RT-DeVIC and SMILE. The risk of CNS relapse is an important consideration in advanced ENKTL.

Prognostic value of the Kyoto Prognostic Index in higher-risk diffuse large B-cell lymphomas treated by upfront autologous stem cell transplantation in JCOG0908 trial.

BACKGROUND: There is currently no standard prognostic model optimized for the patients with diffuse large B-cell lymphoma (DLBCL) treated with upfront intensive immunochemotherapy including autologous stem cell transplantation (ASCT). The Kyoto Prognostic Index (KPI) has been proposed as a novel prognostic model for DLBCL, which can accurately identify especially high-risk patients. In this study, we investigated the prognostic value of the KPI in JCOG0908 trial in which higher-risk DLBCL patients defined by the conventional International Prognostic Index (IPI) were treated with upfront high dose therapy followed by ASCT. METHODS: Fifty-eight patients with DLBCL, not otherwise specified, enrolled in JCOG0908 and confirmed by the central pathological review were analyzed. The Kaplan-Meier method was used to estimate the probabilities of overall survival (OS) and progression-free survival (PFS). We compared the discrimination ability of the KPI with that of the IPI. RESULTS: According to KPI, 3-year OS and PFS rates were 86.7% and 76.7% in low-intermediate, 73.3% and 60.0% in high-intermediate, and 61.5% and 46.2% in high-risk group. According to IPI, 3-year OS and PFS rates were 75.0% and 50.0% in low-intermediate, 82.9% and 74.3% in high-intermediate, and 63.6% and 54.5% in high-risk group. The concordance-indices of KPI and IPI were 0.642 and 0.580 for OS and 0.606 and 0.606 for PFS. CONCLUSIONS: The KPI may be a suitable predictor of outcome than the IPI for patients with higher-risk DLBCL treated with upfront intensive immunochemotherapy including ASCT.

Single response assessment of transplant-ineligible multiple myeloma: a supplementary analysis of JCOG1105 (JCOG1105S1).

BACKGROUND: The International Myeloma Working Group response criteria require two consecutive assessments of paraprotein levels. We conducted an exploratory analysis to evaluate whether a single response assessment could be a substitute for the International Myeloma Working Group criteria using data from JCOG1105, a randomized phase II study on melphalan, prednisolone and bortezomib. METHODS: Of 91 patients with transplant-ineligible newly diagnosed multiple myeloma, 79 patients were included. We calculated the kappa coefficient to evaluate the degree of agreement between the International Myeloma Working Group criteria and the single response assessment. RESULTS: Based on the International Myeloma Working Group criteria, 11 (13.9%), 20 (25.3%), 36 (45.6%) and 12 (15.2%) patients had stringent complete response/complete response, very good partial response, partial response and stable disease, respectively. Based on the single response assessment, 17 (21.5%), 19 (24.1%), 35 (44.3%) and 8 (10.1%) patients had stringent complete response/complete response, very good partial response, partial response and stable disease, respectively. The kappa coefficient was 0.76 (95% confidence interval, 0.65-0.88), demonstrating good agreement. The single response assessment was not inferior to the International Myeloma Working Group criteria in the median progression-free survival (3.8 and 2.9 years) in stringent complete response/complete response patients, suggesting that the single response assessment was not an overestimation. CONCLUSIONS: The single response assessment could be a substitute for the current International Myeloma Working Group criteria for transplant-ineligible newly diagnosed multiple myeloma.

[A rare synchronous occurrence of multiple myeloma and pulmonary adenocarcinoma with multiple solitary extramedullary plasmacytomas of the liver].

We report the case of a 62-year-old woman with multiple liver tumors. She was diagnosed with synchronous occurrence of multiple myeloma (MM) and primary pulmonary adenocarcinoma 4 years ago. She was treated with bortezomib and dexamethasone for MM, and then she underwent thoracoscopic lobectomy. After the surgery, she received autologous peripheral blood stem cell transplantation. However, recurrence of MM was observed 9 months later. She received multiple chemotherapies for MM, but the effect was limited. Meanwhile, brain metastasis of pulmonary adenocarcinoma was observed; therefore, she underwent surgical resection and received radiation therapy. Furthermore, she had elevated levels of liver enzymes, and ultrasonography revealed multiple liver tumors. Because of thrombocytopenia, liver biopsy could not be performed, and chemotherapies for MM did not improve the tumors. Therefore, we clinically determined that the liver tumors were metastatic pulmonary adenocarcinomas. The epidermal growth factor receptor mutation was present in the pulmonary adenocarcinoma, so gefitinib was administered. However, the tumors were uncontrollable and the patient died within 1 month. From autopsy, the liver lesion was confirmed to be MM. Synchronous occurrence of MM and other primary cancers is very rare, and no standard treatment has yet been established. Thus, it is crucial to accumulate synchronous cases and develop treatment methods in the future.

R-CHOP-14 versus R-CHOP-14/CHASER for upfront autologous transplantation in diffuse large B-cell lymphoma: JCOG0908 study.

The efficiency of upfront consolidation with high-dose chemotherapy/autologous stem-cell transplantation (HDCT/ASCT) for newly diagnosed high-risk diffuse large B-cell lymphoma (DLBCL) may be influenced by induction chemotherapy. To select better induction chemotherapy regimens for HDCT/ASCT, a randomized phase II study was conducted in high-risk DLBCL patients having an age-adjusted International Prognostic Index (aaIPI) score of 2 or 3. As induction chemotherapy, 6 cycles of R-CHOP-14 (arm A) or 3 cycles of R-CHOP-14 followed by 3 cycles of CHASER (arm B) were planned, and patients who responded proceeded to HDCT with LEED and ASCT. The primary endpoint was 2-y progression-free survival (PFS), and the main secondary endpoints included overall survival, overall response rate, and adverse events (AEs). In total, 71 patients were enrolled. With a median follow-up of 40.3 mo, 2-y PFS in arms A and B were 68.6% (95% confidence interval [CI], 50.5%-81.2%) and 66.7% (95% CI: 48.8%-79.5%), respectively. Overall survival at 2 y in arms A and B was 74.3% (95% CI: 56.4%-85.7%) and 83.3% (95% CI: 66.6%-92.1%). Overall response rates were 82.9% in arm A and 69.4% in arm B. During induction chemotherapy, 45.7% and 75.0% of patients in arms A and B, respectively, had grade ≥ 3 non-hematologic toxicities. One patient in arm A and 6 in arm B discontinued induction chemotherapy due to AEs. In conclusion, R-CHOP-14 showed higher 2-y PFS and less toxicity compared with R-CHOP-14/CHASER in patients with high-risk DLBCL, suggesting the former to be a more promising induction regimen for further investigations (UMIN-CTR, UMIN000003823).

Activated oncogenic pathways and therapeutic targets in extranodal nasal-type NK/T cell lymphoma revealed by gene expression profiling.

We performed comprehensive genome-wide gene expression profiling (GEP) of extranodal nasal-type natural killer/T-cell lymphoma (NKTL) using formalin-fixed, paraffin-embedded tissue (n = 9) and NK cell lines (n = 5) in comparison with normal NK cells, with the objective of understanding the oncogenic pathways involved in the pathogenesis of NKTL and to identify potential therapeutic targets. Pathway and network analysis of genes differentially expressed between NKTL and normal NK cells revealed significant enrichment for cell cycle-related genes and pathways, such as PLK1, CDK1, and Aurora-A. Furthermore, our results demonstrated a pro-proliferative and anti-apoptotic phenotype in NKTL characterized by activation of Myc and nuclear factor kappa B (NF-κB), and deregulation of p53. In corroboration with GEP findings, a significant percentage of NKTLs (n = 33) overexpressed c-Myc (45.4%), p53 (87.9%), and NF-κB p50 (67.7%) on immunohistochemistry using a tissue microarray containing 33 NKTL samples. Notably, overexpression of survivin was observed in 97% of cases. Based on our findings, we propose a model of NKTL pathogenesis where deregulation of p53 together with activation of Myc and NF-κB, possibly driven by EBV LMP-1, results in the cumulative up-regulation of survivin. Down-regulation of survivin with Terameprocol (EM-1421, a survivin inhibitor) results in reduced cell viability and increased apoptosis in tumour cells, suggesting that targeting survivin may be a potential novel therapeutic strategy in NKTL.

Prognostic Impact of a Body Mass Index Decrease during First Chemotherapy in Patients with Advanced Follicular Lymphoma.

Objective Follicular lymphoma (FL) is an indolent B-cell malignancy, usually treated by immunochemotherapy in advanced-stage and high-tumor-burden cases. Although some reports have shown no significant relationship between the pre-treatment body mass index (BMI) and the overall survival (OS) in FL, little is known regarding BMI changes during chemotherapy. We analyzed the impact of a BMI decrease during chemotherapy on the OS in FL patients. Methods We retrospectively analyzed 56 patients with untreated advanced FL who underwent chemotherapy at our institute between July 2009 and December 2020. The BMI change was defined based on the BMI before and at three months after the first chemotherapy session. The cut-off for a BMI decrease was set at 1.42 kg/m2 according to the receiver operating characteristics curve for the OS. We compared the survival outcome between two BMI groups based on this cut-off. Results A BMI decrease was significantly associated with a worse OS (5-year OS: 86.7% vs. 60.5%, p=0.019), although the pre-treatment BMI showed no significant relationship with the survival. The adverse impact of a BMI decrease remained in a multivariate analysis for the OS (hazard ratio, 3.972; p=0.045). The decreased-BMI group tended to show a higher cumulative incidence of early-onset histological transformation (HT) than the non-decreased-BMI group (20% vs. 0.0%). A BMI decrease during chemotherapy in previously untreated FL patients might reflect the hyperactivation of tumor-induced metabolism related to HT. Conclusion A BMI decrease during chemotherapy might be an independent adverse prognostic factor in FL patients. BMI changes in addition to the condition of FL patients should be monitored during chemotherapy.

A multicenter, phase II study of full-dose THP-COP therapy for elderly patients with newly diagnosed, advanced-stage, aggressive non-Hodgkin lymphoma.

The cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) regimen, containing doxorubicin (DXR), which is a key drug for aggressive non-Hodgkin lymphoma (NHL), is a standard chemotherapeutic regimen; however, its administration in elderly patients is often intolerable. Pirarubicin (tetrahydropyranyl adriamycin [THP]) is an anthracycline developed in Japan. We have conducted a phase II trial of a full-dose THP-COP (modified CHOP regimen with DXR replaced by THP) regimen for elderly patients with newly diagnosed, advanced-stage, aggressive NHL. Patients aged 70-79 years old with previously untreated NHL according to the Working Formulation (D through H and J), disease stage I with a bulky mass or stage II-IV, and performance status of 0-1 were eligible. The THP-COP regimen, which consisted of 750-mg/m2 cyclophosphamide, 50-mg/m2 THP, 1.4-mg/m2 vincristine (capped at 2.0 mg) on day 1, and 100-mg prednisolone daily on days 1 to 5, was delivered every 3 weeks for 6 cycles. The primary endpoint was complete response (CR) rate. Twenty-nine patients were enrolled in the study. The CR rate was 65.5% (95% confidence interval, 45.7-82.1%). The 3-year failure-free and overall survival rates were 54.1% and 53.9%, respectively. The most frequent observed grade 3 or 4 toxicity was neutropenia, which occurred in 80% of the patients. Grade 3 cardiac dysfunction was observed in one patient. The full-dose THP-COP regimen exhibited similar efficacy and safety, and a tendency for less cardiac toxicity, when compared with the standard CHOP regimen in elderly Japanese patients with newly diagnosed, advanced-stage, aggressive NHL.

Establishment of an ATLL cell line (YG-PLL) dependent on IL-2 and IL-4, which are replaced by OX40-ligand+ HK with poly-L-histidine and dermatan sulfate.

We established an IL-2 and IL-4 (IL2/4) - dependent adult T-cell leukemia/lymphoma (ATLL) cell line (YG-PLL) by adding poly-L-lysine (PLL) to the culture medium. YG-PLL originates from lymphoma cells and contains a defective HTLV-I proviral genome. Although YG-PLL cannot survive without IL-2/4, the follicular dendritic cell (FDC)-like cell line HK expressing OX40-ligand gene (OX40L+HK) inhibited their death in the presence of soluble neutral polymers. After the prevention of cell death, YG-PLL proliferated on OX40L+HK without IL2/4 in the presence of two kinds of positively or negatively charged polymers. In particular, dermatan sulfate and poly-L-histidine supported growth for more than 4 months. Therefore, the original lymphoma cells proliferated transiently in the presence of IL2/4, and their growth arrest was inhibited by the addition of PLL. Furthermore, YG-PLL lost IL2/4 dependency by the following 3-step procedure: preculture with IL2/4 and neutral polymers, 3-day culture with neutral polymer on OX40L+HK to inhibit cell death, and co-culture with OX40L+HK in the presence of the positively and negatively charged polymers. The extracellular environment made by soluble polymers plays a role in the growth of ATLL in vitro.

A multicenter, phase II study of R-THP-COP therapy for elderly patients with newly diagnosed, advanced-stage, indolent B-cell lymphoma.

The optimal combined chemotherapy regimen with rituximab has yet to be established for elderly patients with advanced-stage indolent B-cell lymphoma (B-NHL). A multicenter study was performed to evaluate the efficacy and toxicity of R-THP-COP therapy in elderly patients (aged 70-79 years) with newly diagnosed advanced-stage indolent B-NHL using the complete response rate (%CR) as the primary endpoint. Patients with newly diagnosed, clinical stage III/IV, indolent B-NHL, aged 70-79 years, with a performance status of 0-2 were eligible for this study. R-THP-COP consists of 375 mg/m2 of rituximab, 50 mg/m2 of pirarubicin, 750 mg/m2 of cyclophosphamide, 1.4 mg/m2 of vincristine, and 100 mg/day of oral prednisolone for 5 days. This study was discontinued due to poor accrual after the enrollment of 18 patients, although the planned sample size was 40 patients. The numbers of patients with follicular lymphoma, mucosa-associated lymphoid tissue lymphoma, and mantle cell lymphoma were 16, 1, and 1, respectively. The median age was 73 (range, 70 to 79) years. The %CR including unconfirmed CR was 45% (95% confidence interval: 25-66%) and the overall response rate was 72%. The estimated 5-year overall survival and progression-free survival rates were 55% and 28%, respectively. The major toxicity observed was grade 4 neutropenia (94%). Grade 4 non-hematological toxicities were not observed and no patients developed grade 3/4 cardiac toxicities. This phase II study provides useful information regarding the efficacy and toxicity of R-THP-COP therapy for patients aged 70 years or older with newly diagnosed, advanced-stage, indolent B-NHL, although the sample size was small.

Development of novel humanized anti-CD20 antibodies based on affinity constant and epitope.

We describe novel humanized anti-CD20 monoclonal antibodies (mAbs) developed for therapeutic use on the basis of their physicochemical properties and cellular cytotoxicity. A distinct correlation between apparent dissociation constants (K(d)) and apoptotic activity for eight murine anti-CD20 mAbs (OUBM1-OUBM8) and previously-developed murine anti-CD20 mAbs enabled us to categorize anti-CD20 mAbs into two groups. Group A mAbs had lower K(d) values and did not induce definite apoptosis, while Group B mAbs had greater K(d) values and did induce definite apoptosis. A murine version mAb of rituximab, 2B8, belongs to Group B. An epitope analysis showed that the epitope of two murine mAbs, OUBM3 and OUBM6, differed from that of 2B8 or 2F2 (ofatumumab). Two mAbs, OUBM3 from Group A and OUBM6 from Group B, were selected and humanized. As expected, the humanized OUBM3 with the lower K(d) did not induce apoptosis, while the humanized OUBM6 (hOUBM6) with the greater K(d) did. Both hOUBM3 and hOUBM6 induced highly-effective, complement-dependent cytotoxicity and antibody-dependent, cell-mediated cytotoxicity against Burkitt's and follicular lymphomas. Importantly, hOUBM6 exhibited cellular cytotoxicity against diffuse, large B cells that are less effectively depleted by rituximab and also exhibited effective cytotoxicity against tumor cells from human CD20(+) leukemia and lymphoma patients. These results suggest the potential impact of the further development of our anti-CD20 mAbs. Our study shows that the selection of mAbs based on their physicochemical parameters, followed by the biological activity assessment for the selected mAbs, is a rational and efficient approach for pharmaceutical mAb development.

Primary gastric diffuse large B-cell Lymphoma (DLBCL): analyses of prognostic factors and value of pretreatment FDG-PET scan.

OBJECTIVES: We report a single institution experience with gastric diffuse large B-cell lymphoma (DLBCL) in an attempt to evaluate the roles of different treatment modalities, to assess the value of pretreatment positron emission tomography (PET) scan, and to identify potential prognostic factors. METHODS: Among 384 patients diagnosed with DLBCL between 1995 and 2008, 75 patients had primary gastric DLBCL and were reviewed and analyzed. RESULTS: The median age was 66. International prognostic index (IPI) risk was low in 52%, low-intermediate in 23%, high-intermediate in 9%, and high in 16%. Pretreatment PET scan was highly sensitive in detecting gastric lesions except stage I gastric DLBCL without detectable mass by CT or gastroscopy. As a general rule, patients with limited-stage disease were treated with three times of CHOP (with or without rituximab) and radiotherapy, and those with advanced-stage disease were treated with eight cycles of CHOP (with or without rituximab), and radiotherapy was given to residual diseases after chemotherapy. Three-year overall survival (OS) rate was 78%. Multivariate analysis revealed that low albumin, hemoglobin <12.0 g/dL, and treatment without rituximab were independently associated with shorter OS. Low albumin, hemoglobin <12.0 g/dL,and advanced stage were independently associated with shorter progression-free survival. CONCLUSION: We showed the survival benefit of rituximab and potential prognostic value of pretreatment hemoglobin and serum albumin levels in gastric DLBCL.

Phase II study of a salvage regimen using cyclophosphamide, high-dose cytarabine, dexamethasone, etoposide, and rituximab in patients with relapsed or refractory B-cell non-Hodgkin's lymphoma.

The management of relapsed or refractory B-cell non-Hodgkin's lymphoma (B-NHL) remains challenging. We investigated the efficacy and safety of salvage chemoimmunotherapy (CHASER) in patients with relapsed or refractory B-NHL who had radiographically measurable disease and adequate major organ function. The CHASER treatment consisted of: rituximab 375 mg/m(2), day 1; cyclophosphamide 1200 mg/m(2), day 3; cytarabine 2 g/m(2), days 4 and 5; etoposide 100 mg/m(2), days 3-5; and dexamethasone 40 mg, days 3-5. The treatment was repeated every 3 weeks up to a total of four courses in the absence of disease progression. Thirty-two patients were enrolled and received a median of four courses of treatment (range 1-4 courses) per patient. Twenty patients (63%) were previously treated with rituximab-containing regimens. The median age was 54 years (range 28-67 years). The treatment was generally well tolerated, with major toxicities being grade 4 neutropenia (n = 32), thrombocytopenia requiring transfusion (n = 28), and grade 3 transaminase elevation (n = 2). Overall response rates in the entire group, and in patients with indolent (n = 17) and aggressive (n = 15) diseases were 84%, 100% and 67%, respectively. Responses were observed similarly in patients with (n = 20) and without (n = 12) previous rituximab exposure (85% and 83%, respectively). Stem cell harvest was successful in 19 of 22 patients. The median time to treatment failure for the entire group was 24.5 months. This promising result of high activity and favorable toxicity profile warrants further investigation in large-scale multicenter trials.

Phase I and II pharmacokinetic and pharmacodynamic study of the proteasome inhibitor bortezomib in Japanese patients with relapsed or refractory multiple myeloma.

The purpose of this phase I and II study was to evaluate the safety, pharmacokinetics, pharmacodynamics, and efficacy of bortezomib in Japanese patients with relapsed or refractory multiple myeloma. This was a dose-escalation study designed to determine the recommended dose for Japanese patients (phase I) and to investigate the antitumor activity and safety (phase II) of bortezomib administered on days 1, 4, 8, and 11 every 21 days. Thirty-four patients were enrolled. A dose-limiting toxicity was febrile neutropenia, which occurred in one of six patients in the highest-dose cohort in phase I and led to the selection of 1.3 mg/m(2) as the recommended dose. Adverse events >or= grade 3 were rare except for hematological toxicities, although there was one fatal case of interstitial lung disease. The overall response rate was 30% (95% confidence interval, 16-49%). Pharmacokinetic evaluation showed a biexponential decline, characterized by a rapid distribution followed by a longer elimination, after dose administration, whereas the area under the concentration-time curve increased proportionately with the dose. Bortezomib was effective in Japanese patients with relapsed or refractory multiple myeloma. A favorable tolerability profile was also seen, although the potential for pulmonary toxicity should be monitored closely. The pharmacokinetic and pharmacodynamic profiles of bortezomib in the present study warrant further investigations, including more relevant administration schedules.

De novo CD5+ diffuse large B-cell lymphoma: results of a detailed clinicopathological review in 120 patients.

BACKGROUND: De novo CD5-positive diffuse large B-cell lymphoma (CD5(+) DLBCL) is clinicopathologically and genetically distinct from CD5-negative (CD5(-)) DLBCL and mantle cell lymphoma. The aim of this retrospective study was to clarify the histopathological spectrum and obtain new information on the therapeutic implications of CD5(+) DLBCL. DESIGN AND METHOD: From 1984 to 2002, 120 patients with CD5(+) DLBCL were selected from 13 collaborating institutes. We analyzed the relationship between their morphological features and long-term survival. The current series includes 101 patients described in our previous study. RESULTS: Four morphological variants were identified: common (monomorphic) (n=91), giant cell-rich (n=13), polymorphic (n=14), and immunoblastic (n=2). Intravascular or sinusoidal infiltration was seen in 38% of the cases. BCL2 protein expression in CD5(+) DLBCL was more frequent than in CD5(-) DLBCL (p=0.0003). Immunohistochemical analysis in 44 consecutive cases of CD5(+) DLBCL revealed that 82% of these cases (36/44) were non-germinal center B-cell type DLBCL. The 5-year overall survival rate of the patients with CD5(+) DLBCL was 38% after a median observation time of 81 months. Patients with the common variant showed a better prognosis than those with the other three variants (p=0.011), and this was confirmed on multivariate analysis. Overall, 16 patients (13%) developed central nervous system recurrence. CONCLUSIONS: Our study revealed the morphological spectrum of CD5(+) DLBCL, found that the incidence of central nervous system recurrence in this form of lymphoma in high, confirmed that CD5(+) DLBCL frequently expresses BCL2 protein and showed that it is mainly included in the non-germinal center B-cell type of DLBCL.

Low absolute lymphocyte count is a poor prognostic marker in patients with diffuse large B-cell lymphoma and suggests patients' survival benefit from rituximab.

OBJECTIVES: To evaluate the prognostic value of absolute lymphocyte count (ALC) at diagnosis in patients with diffuse large B-cell lymphoma (DLBCL). METHODS: In a large cohort of patients with DLBCL treated with CHOP (n = 119) or RCHOP (n = 102) in our institution, we evaluated the prognostic value of ALC at diagnosis with regards to treatment response, overall (OS) and progression-free survival (PFS). Use of rituximab, all International Prognostic Index (IPI) determinants, beta2microglobulin level, presence of B symptoms or bulky disease, and ALC were evaluated. RESULTS: Low ALC (<1.0 x 10(9)/L) was associated with advanced stage, performance status >or=2, elevated lactate dehydrogenase, number of extranodal involvement >or=2, B symptoms, elevated beta2microglobulin and higher IPI risk group. Low ALC was associated with lower CR rate by univariate analysis (odds ratio = 3.29, P = 0.024) but not by multivariate analysis. By univariate analysis using Cox proportional hazard model, low ALC was associated with shorter OS [hazard ratio (HR) = 2.89, P < 0.001] and PFS (HR = 2.91, P < 0.001). Multivariate analysis revealed that low ALC was associated with shorter OS (HR = 2.51, P = 0.003) and PFS (HR = 2.72, P < 0.001), independent of above-mentioned parameters. Subclass analyses revealed that the use of rituximab improves OS in patients with low ALC (HR = 0.42, P = 0.05) but not in those with high ALC (HR = 0.83, P = 0.71). This observation was most obvious in patients with higher IPI score. CONCLUSION: Low ALC is a poor prognostic marker in patients with DLBCL and suggests patients' survival benefit from rituximab.