High-risk International Prognostic Index Research Articles

Prognostic Significance of Interim 18f-FDG PET/CT for the Treatment of Diffuse Large B-Cell Lymphoma In the Post-Rituximab Era.

AbstractAbstract 179918F-fluoro-2-dexoy-D-glucose-positron emission tomography (FDG-PET)/computerized tomography (CT) has been used for staging and monitoring responses to treatment in patients with diffuse large B cell lymphoma (DLBCL). The sequential interim PET/CT was prospectively investigated to determine whether it provided additional prognostic information and could be a positive predictable value within patients with the same international prognostic index (IPI) after the use of rituximab in DLBCL. Patients and methods:One hundred and sixty-one patients with newly diagnosed DLBCL were enrolled between August 2004 and December 2009 at a single institution. The assessment of the PET/CT was performed at the time of diagnosis and mid-treatment of R-CHOP chemotherapy. The clinical stage and response of the patients were assessed according to revised response criteria for aggressive lymphomas (Cheson, J Clin Oncol, 2007). The positivity of interim PET/CT was determined based on the semi-quantitative assessment of the maximal standardized uptake value (SUVmax cut-off value of 3.0). Results:Sixty-seven patients (41.6%) presented in advanced stage disease and 27 (16.8%) had bulky lesions. At diagnosis, 53 patients (32.9%) were classified as high/high-intermediate risk by the IPI and two patients could not check the interim response due to treatment-related mortality (TRM). Forty-three patients (26.7%) continued to have positive metabolic uptakes with a significantly high relapse rate (62.8%) compared to the patients with a negative interim PET/CT (12.1%) (P<0.01). After a median follow-up of 30.8 months, the positivity of interim PET/CT was found to be a prognostic factor for both OS and PFS, with a hazard ratio of 4.07 (2.62 – 6.32) and 5.46 (3.49 – 8.52), respectively. In the low-risk IPI group, the 3-year OS and PFS rate was significantly different in the patients with positive (53.3 and 52.5%) and negative (93.8 and 88.3%) interim PET/CT, respectively (P<0.01). These significant prognostic differences of interim PET/CT responses were consistent with the results of the patients with high-risk IPI group (P< 0.01). Conclusions:Interim PET/CT scanning had a significant predictive value for disease progression and survival of DLBCL in post-rituximab treatment; it might be the single most important determinant of clinical outcome in patients with the same IPI risk. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Prognostic impact of protein kinase C β II expression in R-CHOP-treated diffuse large B-cell lymphoma patients

Development of targeted agents for the treatment of diffuse large B-cell lymphoma includes clinical evaluation of enzastaurin, an agent that suppresses signaling through protein kinase C-β and AKT pathways. To determine whether protein kinase C-β expression has prognostic significance for diffuse large B-cell lymphoma patients treated with immunochemotherapy, we analyzed the expression of protein kinase C-β II, BCL-2 and cell of origin immunohistochemically from pretreatment samples of 95 diffuse large B-cell lymphoma patients. All patients received rituximab with CHOP or CHOEP. According to Kaplan–Meier analyses, overall survival at 3 years was better among the patients with low than high protein kinase C-β II protein levels (94 vs 76%, P=0.036). The prognostic value of protein kinase C-β II expression on survival was seen in the patients with low and high International Prognostic Index risk groups, and in all molecular entities. Gene expression data from an independent set of 233 diffuse large B-cell lymphoma patients treated with a combination of rituximab and CHOP-like chemotherapy was analyzed in comparison. Accordingly, a better 3-year overall survival was observed among the subgroup with low protein kinase C-β II mRNA levels (84 vs 68%, P=0.005). In multivariate analysis with cell of origin, protein kinase C-β II mRNA expression remained as an independent predictor for overall survival. Together, the data show that protein kinase C-β II expression has prognostic significance in diffuse large B-cell lymphoma patients treated with immunochemotherapy.

Brief-Duration Rituximab/Chemotherapy Followed by Maintenance Rituximab in Patients With Diffuse Large B-Cell Lymphoma Who Are Poor Candidates for R-CHOP Chemotherapy: A Phase II Trial of the Sarah Cannon Oncology Research Consortium

Patients with diffuse large B-cell lymphoma (DLBCL) who are very elderly or have poor performance status are difficult to treat with a full course of R-CHOP (rituximab plus cyclophosphamide/doxorubicin/vincristine/ prednisone) therapy. In this phase II trial, we treated this group of patients with a novel regimen containing 3 courses of rituximab/chemotherapy followed by maintenance rituximab. Patients with newly diagnosed stage II-IV DLBCL were eligible if they were considered poor candidates for 6-8 cycles of R-CHOP therapy. Patients who were eligible for anthracycline therapy received 3 cycles of rituximab plus cyclophosphamide/ mitoxantrone/vincristine/prednisone (CNOP); the remainder of patients received R-CVP (rituximab plus cyclophosphamide/ vincristine/prednisone). Patients without progression after completion of 3 cycles received 4 courses of maintenance rituximab (375 mg/m2 weekly x 4, repeated every 6 months) for 24 months. Between May 2003 and July 2007, 51 patients were enrolled. The median age was 78 years, and 43% of patients were > 80 years of age. Nineteen patients (37%) had Eastern Cooperative Oncology Group performance status of 2, and 72% had high-intermediate or high-risk International Prognostic Index scores. After a median follow-up of 48 months, the 2-, 3-, and 4-year progression-free survival rates are 71%, 65%, and 56%, respectively. The 2-, 3-, and 4-year overall survival rates are 72%, 67%, and 67%, respectively. Treatment was well tolerated, with few severe toxicities and no treatment-related deaths. This abbreviated course of rituximab/chemotherapy, followed by maintenance rituximab, was active and well tolerated in these very elderly patients. Brief-duration rituximab/chemotherapy as well as maintenance rituximab merit further evaluation in this setting.

Doxorrubicina liposomal no pegilada en combinación con ciclofosfamida, vincristina, prednisona y rituximab en el tratamiento de linfomas no hodgkinianos: estudio de 26 pacientes

Background and objectives Non-pegylated liposomal doxorubicin is associated with lower cardiac toxicity than conventional doxorubicin, and for that reason it has been used in the treatment of non-Hodgkin's lymphoma (NHL) in old patients or patients with cardiac disease. The objective of this study was to evaluate the efficacy and safety of chemotherapy schedules including non-pegylated liposomal doxorubicin in patients with NHL. Patients and methods Retrospective study of NHL patients treated with non-pegylated liposomal doxorubicin in two hospitals. In each patient demographic data, clinical and biological variables, as well as therapy, response and toxicity were recorded. Results Twenty-six patients were included, 14 (58%) of them were women. Median age was 76 years (range 42–86). The most frequent histological diagnosis was diffuse large B cell lymphoma (DLBCL, 20 patients). The stage disease at diagnosis was III/IV in 19 (73%) patients whereas 12 (57%) of the 21 patients with DLBCL and grade 3 follicular lymphoma had a high-risk International Prognostic Index. Three patients had a left ventricular ejection fraction lower than 50% at the time of starting treatment. The most frequent cardiovascular risk factor was hypertension (50% of the patients) and 6 (23%) had previous heart disease. In all cases non-pegylated liposomal doxorubicin was administered as part of the R-COMP schedule (rituximab, cyclophosphamide, vincristin, non-pegylated liposomal doxorubicin and prednisone), in 20 cases (73%) as first-line treatment and in the remaining 6 as salvage therapy. Two patients died after the first cycle of chemotherapy (one because of sudden death and the other due to disease progression). Eleven (61%) out of the 18 patients receiving R-COMP as first-line therapy achieved a complete response (CR), 5 (28%) achieved partial response (PR) and 2 showed progression. Only one out of the 6 patients receiving R-COMP as salvage therapy achieved CR, whereas 3 had PR and 2 did not respond. Grade 3 or 4 neutropenia was observed in 11 (46%) patients and febrile neutropenia in 10 (42%), while only one patient developed grade 4 thrombocytopenia. The median overall survival was 50,7 months (95% confidence interval [95% CI] 8–93.3) and the median disease free survival was 18,4 months (95% CI 18.1–18.7). Conclusions In this cohort of patients, most of them old and with cardiovascular risk factors, the administration of non-pegylated liposomal doxorubicin as part of R-COMP regimen was effective and safe.

No Benefit from Rituximab Containing Regimens in Patients with Primary Extranodal Diffuse Large B-Cell Lymphoma

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous category of lymphoid tumors that comprises different clinical forms not fully recognized in the WHO classification. In this regard, extranodal (EN) DLBCLs have particular clinicobiological features and outcome, sometimes related to the specific site where the lymphoma arises. Nowadays, rituximab plus chemotherapy (CT) is the gold-standard in the treatment of DLBCL. However, the superiority of rituximab-CT (R-CT) over CT alone has not been addressed for all the clinical subsets of the disease and, in fact, the clinical role of the new therapies might be different for primary nodal or EN DLBCLs. The aim of this study was to assess the impact of rituximab in patients suffering from nodal or EN DLBCL. Two-hundred and thirty non-immunocompromised patients (112M/118F; median age, 61 years) diagnosed with CD20+DLBCL in a single institution between 1997 and 2006 (five years before and after establishing R-CT as the standard treatment in DLBCL) and treated with adriamycin-containing regimens were the subject of the present study. The series included 148 primary nodal and 82 EN DLBCL. Patients with primary CNS lymphoma were excluded and lymphomas arising at Waldeyer ring were considered as nodal DLBCL. The main EN sites were GI (n=26), bone (n=13), soft tissue (n=13), lung/pleura (n=9), liver (n=9), and other (n=12). Main clinico-biological and evolutive variables were analyzed. One hundred nineteen patients received only CT and 111 R-CT. Eighty-seven cases with available information were assigned to germinal center B-cell-like (GCB) (41%) or non-GCB (59%) groups according to the Hans method (Blood 2004; 103:275–82) based on CD10, BCL6 and MUM1 expression. Main initial features, including the primary nodal or EN origin, international prognostic index (IPI), and GCB/non-GCB categories were similar for CT and R-CT groups. No correlation was observed between the GCB/non-GCB groups and the primary site of the tumor, although nodal lymphomas more frequently expressed MUM1 than EN (69% vs. 31%, respectively; p=0.01). CR rate and 5-year overall survival (OS) according to the treatment arm (CT vs. R-CT) is detailed for the whole series and for the nodal and EN groups in the table and OS curves depicted in the figure. In the whole series, variables predicting poor OS in the multivariate analysis were high-risk IPI (RR 2.5; p<0.001), primary nodal involvement (RR 1.6; p=0.04) and no R-CT treatment (RR 1.9; p=0.002). In the nodal group, IPI and no R-CT maintained the prognostic value, whereas in the primary EN only IPI predicted OS. Moreover, no difference in OS was observed according to the nodal or EN origin in those patients receiving R-CT. Biological subtypes GCB vs. non-GCB did not add predictive information neither in the whole series nor in the nodal or EN groups. In conclusion, patients with primary EN DLBCL seem to have little benefit from the use of R-CT. Nevertheless, this intriguing observation should be confirmed in further prospective studies.Complete response CR (%)5-years OS (%)CTR-CTCTR-CTAll cases (n=230)5979*4670*Primary nodal (n=148)5478*3471*Primary extranodal (n=82)68787069*p<0.002 R-CT vs. CT [Display omitted]

PRDM1 is involved in chemoresistance of T-cell lymphoma and down-regulated by the proteasome inhibitor

AbstractThe positive regulatory domain I (PRDM1) is a master regulator of terminal B-cell differentiation. However, PRDM1 is not B-cell specific. To determine its role in T-cell lymphoma, PRDM1 expression was investigated in 60 patients. PRDM1α and PRDM1β transcripts were detected in laser-microdissected T-lymphoma cells in 27 and 14 patients, respectively, mostly in cases with IRF4 expression. PRDM1β was associated with increased c-MYC expression. PRDM1β-positive patients displayed advanced Ann Arbor stage and high-risk International Prognostic Index and were linked to short survival times. In vitro, PRDM1β was related to resistance to chemotherapeutic agents and could be down-regulated by the proteasome inhibitor bortezomib. Kinetic studies showed that bortezomib down-regulation of PRDM1β preceded decreased IRF4 and c-MYC expression. An earlier retaining of cytoplasmic IκBα in bortezomib-treated cells was revealed, concomitant with blockade of NF-κB nuclear translocation. These results demonstrate the involvement of PRDM1β in T-cell lymphoma, with possible therapeutic interference by the proteasome inhibitor.

Central nervous system involvement in mantle cell lymphoma

BackgroundExtranodal involvement, including central nervous system (CNS), is a frequent event in patients with mantle cell lymphoma (MCL). However, the incidence, risk factors, and impact on outcome remain controversial. Patients and methodsMain clinical, biological, and evolutive features of 82 patients (60 males/22 females; median age: 61 years) diagnosed with MCL (blastoid, 26%) in a single institution were analyzed for risk of CNS involvement and prognosis. ResultsMost patients had advanced stage and intermediate or high-risk International Prognostic Index (IPI). Eleven patients eventually developed CNS involvement with an actuarial 5-year risk of 26% (95% confidence interval 10% to 42%). In one asymptomatic patient, cerebrospinal fluid infiltration was detected at staging maneuvers (1/62; 1.6%). The remaining 10 patients developed neurological symptoms during the course of the disease (median time from diagnosis, 25 months). Initial variables predicting CNS involvement were blastoid histology, high proliferative index measured by Ki-67 staining, high lactate dehydrogenase (LDH) and intermediate- or high-risk IPI. Histological subtype and serum LDH maintained significance in multivariate analysis. Treatment of CNS infiltration consisted of intrathecal chemotherapy (two cases), and intrathecal chemotherapy plus systemic treatment (seven cases). Median survival after CNS involvement was 4.8 months, patients with this complication having shorter survival than those with no CNS disease. ConclusionThis study confirms the high incidence of CNS involvement in MCL patients. Treatments aimed at preventing this complication are warranted.

Prognostic value of serum soluble interleukin-2 receptor level in patients with diffuse large B cell lymphoma, treated with CHOP- or RCHOP-based therapy

The emergence of rituximab has changed the clinical outcome of patients with B-cell lymphoma, which necessitates reassessment of previously determined prognostic factors. Thus, we evaluated the prognostic significance of serum soluble interleukin-2 receptor (sIL2R) levels in patients with diffuse large B cell lymphoma (DLBCL), treated with CHOP (n = 108) or RCHOP (n = 94). Serum sIL2R level ranged from 316 to 23 800 U/mL (median 1064 U/mL) and levels were generally higher in higher IPI risk group. Multivariate analyses revealed that sIL2R ≥1000 U/mL was associated with shorter progression free survival [hazard ratio (HR) = 2.52, p = 0.011] and overall survival (HR = 2.34, p = 0.037) independent of IPI risk group or rituximab use. Further subgroup analyses revealed that the impact of sIL2R was most apparent in patients with IPI low risk, both in CHOP alone and RCHOP group. Our study confirmed the prognostic value of sIL2R in patients with DLBCL with low International Prognostic Index (IPI) risk, also in the era of rituximab.

R-COMP 21 (Prednisone, Cyclophosphamide, Vincristine, Myocettm and Rituximab) for Frail and Elderly Patients with Aggressive B-Cell Non-Hodgkin Lymphoma: A Pilot Study.

CHOP chemotherapy is the gold standard treatment for patients with indolent and aggressive non-Hodgkin Lymphomas. However, CHOP is frequently poorly tolerated by frail and elderly patients resulting in dose reductions and consequently lower response and cure rates compared to younger patients. The toxicity and efficacy of nonpegylated liposomal doxorubicin (Myocet™) when substituted for conventional doxorubicin in the CHOP 21 regimen (Doxorubicin, Cyclophosphamide, Vincristine, Prednisone given every 3 weeks) were evaluated in the treatment of frail elderly patients with aggressive non-Hodgkin's lymphoma. Twenty patients (median age: 73 years, range 61–82) with diffuse large B cell non-Hodgkin lymphoma, either at diagnosis (15 patients) or relapsing (5 patients), were enrolled in the study. At baseline 14/20 (72%) patients had stage III–IV disease. All patients had one or more comorbidity. Eighteen out of 20 patients (90%) had an intermediate or high risk International Prognostic Index score. The median left ventricular ejection fraction (LVEF) before starting chemotherapy was 62% (range 43–73). A total of 111 chemotherapy cycles were administered, with a median of 6 cycles (range 1–8). Of the cycles administered, 19 (17%) were delayed by haematological toxicity. The relative dose intensity for the regimen was 83%. Toxicity was mainly haematological with grade 3 or 4 neutropenia in 16% of cycles and febrile neutropenia in 5%. However, 3/20 patients presented a grade III–IV WHO toxicity (one fatal pulmonary embolism, one congestive heart failure, one ischemic heart failure) while receiving R-COMP chemotherapy. All but one patient were evaluable for response. 13 out of 19 (68%) had a complete response and an additional 5 patients (26%) achieved a partial response. Of the evaluable patients, only 1/19 (5%) did not respond at all to chemotherapy and rapidly died due to progressive disease. With a median follow-up of 14 months (range 7–18) as of July 2007, 15/18 responding patients (83%) are alive and disease free, as well as 3/18 are alive with active disease. In conclusion, the R-COMP 21 is a very effective regimen with promising response rates in frail and elderly patients with high risk aggressive non-Hodgkin lymphoma. Further studies with a larger cohort of patients are warranted to better define the impact of non pegylated liposomal doxorubicin on overall survival of this setting of elderly and particularly frail patients.

In Patients with Aggressive Non-Hodgkin Lymphoma Treated with CHOP Therapy the Rapidity of Early Response, as Determined by Residual FDG Uptake, Does Not Impact on the Overall Prognosis.

The role of interim FDG PET/CT for the evaluation of response and prediction of prognosis during the treatment of Hodgkin lymphoma has been demonstrated in several studies; however, its function in aggressive non-Hodgkin lymphoma has not been established. This study assesses the value of interim FDG-PET/CT performed after 2 cycles of chemotherapy for predicting response to CHOP-like regimen and prognosis of these patients. There was no change of therapy based on interim PET results. 85 patients (51 males, 34 females; median age 47, range 19–69 years) diagnosed and treated between 2001 and 2006 at the Rambam Medical Center with aggressive lymphoma were evaluated. Patients were treated either with standard CHOP or high-dose cyclophosphamide (3g/m2) CHOP with (n=52) or without (n=33) rituximab. All patients had PET/CT scan after 2 cycles and at the end of therapy. Results of interim PET/CT were considered negative or positive for active disease in the absence or presence of any abnormal FDG uptake. Positive pre-treatment PET/CT study was available in 71 patients. Baseline Gallium67 scan was performed in 9 patients and 5 patients had no baseline study. Only patients with a baseline scintigraphy were included in this analysis. Patients with a negative interim study were defined as negative (group A - 51 patients). Patients with positive interim study showing a decrease in the number or intensity of pre-therapy FDG abnormalities (≤50% of the initial visual uptake) were defined as having improved PET/CT (group B - 27 patients). PET/CT results after 2 cycles and at the end of therapy were assessed for overall (OS) and progression-free survival (PFS), estimated at 30 months. Median follow-up was 22 months (range 4–56 months). 61/85 patients (72%) achieved complete remission and 9/85 patients (10%) achieved partial remission after therapy. Twenty eight patients relapsed or had disease progression within 30 months, with PFS of 61% and OS of 88%. Interim PET was negative in 51 and improved in 27 patients. Tumor progression or relapse occurred in 14/51 (27%) and 9/27 (33%) of these patients, respectively. Thirty month PFS for low risk international prognostic index (IPI), intermediate risk (2) and high risk IPI (3–5) were 82%, 80% and 42%, respectively. Interim PET/CT after 2 cycles of therapy did not correlate with a difference in PFS or OS for patients with improved compared to those with a complete negative study outcome, treated by standard CHOP or CHOP-like protocol (Table). At the end of therapy PET/CT remained positive in 12 patients and became negative in 67 patients in groups A and B. In these two cohorts PFS was 64% and 70% and OS was 81% and 92%, respectively. These data suggest that, in contrast to Hodgkin Disease, an early PET/CT demonstrating residual FDG uptake may not have impact on the long-term outcome. Whether this is due to the different biology of these diseases needs to be determined.30 month PFS30 month OSPredictive value of studyInterim PET with baseline PET or Gallium 67 scan (n=78)n%%%Negative study: Group A (n=51)37/5168%90%*NPV=73%Improved study: Group B (n=27)18/2760%88%**PPV=33%*NPV - negative predictive value; **PPV - positive predictive value

Outcome of poor prognostic phenotype non-Hodgkin lymphoma treatment among HIV-positive patients compared with HIV-negative counterparts in the HAART era: Experience from Hurlingham Oncology Clinic, Nairobi

18535 Background: In human immunedeficiency virus (HIV) related non-Hodgkin’s lymphoma (HIV-NHL) two interrelated life- threatening diseases are considered for treatment decision. Before highly active antiretroviral therapy (HAART), chemotherapy associated toxicity made it difficult for HIV-NHL patients to tolerate treatment. This has remarkably changed in the HAART era. These patients are best treated with standard protocols including: cyclophosphamde, doxorubicin, vincristine and prednisone (CHOP); rituximab-CHOP (R-CHOP): methotrexate, doxorubicin, cyclophosphamide, vincrstine, prednisone and bleomycin (MACOP-B). Methods: We reviewed records of patients with aggressive and highly aggressive phenotype NHLs aged 13 years and above, treated from June 1994 to May 2006. Information included demographic details, pathologic subtype, extent of disease, treatment, outcome. Results: Seventy-five patients - 43 M; 32 F. Age range 13–78 years, median 44.5. Thirty-two (42.7%) were HIV+, 32 (42.7%) HIV- and 11 (14.7%) HIV status undetermined. All HIV+ patients took HAART. Twenty-four (32%) were diffuse large B-cell, 7 (9.3%) transformed follicular, 3 (4%) Burkitt’s 32 (42.7%) only referred to as aggressive/highly aggressive and 9 (12%) others. Thirty-eight (50.7%) were in the high risk International Prognostic Index (IPI) category and 27 (36%) had IPI undetermined. Nine of 21 (42.9%) HIV+ patients had CD4+ cell counts &lt;100/ml. Treatments given upfront were: CHOP-35 patients (46.7%), MACOP-B-14 (18.7%), R-CHOP-11 (14.7%), and dropouts - 8 (10.7%). Seven of 32 (21.9%) HIV-NHL achieved complete remission (CR) vs 24 of 32 (75%) HIV-patients; highly significant (P&lt;0.0001). Five (15.6%) of HIV+ patients had treatment related deaths vs none in HIV- group (P&lt;0.00001). No significant correlation emerged between treatment outcome and IPI score (P= 0.22), or CD4+ cell counts (P = 0.15). HIV+ patients had a median follow-up of 5.5 months, mean of 9; those for HIV- patients were 17 and 30 months respectively; highly significant (P = 0.0036 and 0.0018 respectively). Conclusions: The outcome of treatment was significantly inferior among HIV+ patients. No significant financial relationships to disclose.

CHOP-R + bortezomib as initial therapy for diffuse large B-cell lymphoma (DLBCL)

8031 Background: Bortezomib is a proteasome inhibitor with anti-tumor activity in B cell malignancies. These effects, which may relate to NF-kappaB associated pathways, could sensitize tumor cells to standard chemotherapy-based regimens and enhance efficacy. We report findings of a phase I/II trial of dose-escalated bortezomib + standard CHOP-rituximab in DLBCL patients (accrual of the MCL cohort of this study remains ongoing). Methods: Patients with previously untreated DLBCL (n=40) received CHOP-21 + rituximab (375 mg/m2 each cycle) plus bortezomib at 0.7 mg/m2 (Arm 0, n=4), 1.0 mg/m2 (Arm 1, n=8) or 1.3 mg/m2 (Arm 2, n=28 including phase I and all phase II) on days 1 and 4 of each cycle Results: Median age (n=40) was 58 years (range 21–86), thirty-five subjects (88%) had stage III/IV disease at study entry, and 29 (73%) had elevated serum lactate dehydrogenase (LDH). Patients generally had unfavorable baseline international prognostic index (IPI) scores of 2 in 16 subjects (40%) and 3–5 in 19 subjects (48%). Median follow-up is 21 months (range 9 - 35 months). Treatment was generally well tolerated. Peripheral neuropathy occurred in 22 subjects (55%), with 45% grade 1, 5% grade 2 and 5% grade 3. Grade 4 hematologic toxicity included thrombocytopenia (15%) and leukopenia (15%). Four subjects (3 over age 75 and all with high risk IPI) died prior to first response assessment. Intent to treat (ITT) overall response rate (n=40) is 90% with 68% CR/CRu. For the evaluable subset (n=36), ORR was 100% with CR/CRu 75%. Kaplan-Meier estimate (n=40) of 2-year progression-free survival is 72%. Of all 19 enrolled (ITT) patients in the high-intermediate or high-risk IPI groups, 14 (74%) were alive without progression at last assessment. Correlation of outcome with cell of origin type (activated B cell vs germinal center) is ongoing. Conclusions: Bortezomib can be administered with acceptable toxicity in conjunction with CHOP-R chemotherapy. Efficacy findings with this combination regimen in newly-diagnosed DLBCL are encouraging and warrant further study. No significant financial relationships to disclose.

Retrospective analysis of protein kinase C-beta (PKC-beta) expression in lymphoid malignancies and its association with survival in diffuse large B-cell lymphomas.

BackgroundBoth mechanistic features and recent correlative findings suggest a potential role for protein kinase C-beta (PKC-β) in tumor pathogenesis, particularly in B-cell malignancies. To evaluate the role of this gene in lymphoid malignancies, we analyzed global gene expression data to quantify PKC-β expression across diagnostic groups and, when possible, determined correlations between PKC-β expression and survival.ResultsOur analysis showed that the level of PKC-β expression was highest in chronic lymphocytic leukemia and follicular lymphoma. Within diffuse large-B cell lymphoma (DLBCL), PKC-β expression was significantly higher in activated B-cell- like subtype than germinal center B-cell- like subtype (P < 0.0001). Elevated PKC-β appeared to be associated with worse survival in both of these subtypes. When analyzed within clinically defined risk groups established by the International Prognostic Index (IPI), PKC-β expression was lowest in patients with low IPI scores (0–1). Within intermediate- and high-risk IPI groups, elevated PKC-β expression was associated with worse survival, suggesting that PKC-β may expand the prognostic value of the IPI. Results of global gene expression analyses of DLBCL samples corroborate previous observations that anti-apoptosis, cell proliferation, and B-cell proliferation signaling pathways are functionally related to PKC-β.ConclusionWe present a first detailed pharmacogenomics report comparing PKC-β mRNA expression across different lymphoid malignancies and evaluating it as an outcome predictor. Our findings suggest that DLBCL patients with elevated PKC-β have a worse prognosis, indicating that further evaluation of PKC-β as a chemotherapeutic target for lymphoid malignancies is warranted.ReviewersThis article was reviewed by Dr. Pierre Pontarotti, Dr. Kateryna Makova, and Dr. Matthew Coleman (nominated by Dr. Sandrine Dudoit).

Non-Hodgkin's lymphoma in patients 80 years of age or older

BackgroundVery elderly patients (≥80 years old) with non-Hodgkin's lymphoma (NHL) frequently have co-morbid conditions and are generally excluded from clinical trials or even from treatment. The optimal treatment of these patients is unknown. Patients and methodsWe reviewed the records of 109 patients ≥80 years at diagnosis of NHL (65 F/44 M; median age: 84 years, range; 80–95). ResultsSeventy-eight patients (72%) had aggressive NHL, 25 (23%) had indolent and NHL, eight had unclassified disease. Advanced-stage disease was noted in 54%. Forty patients (39%) had a poor ECOG performance status (PS), and 52 (49%) had an intermediate or high risk International Prognostic Index (IPI). Seventy-nine patients (72%) were treated with chemotherapy and 37 (34%) with radiotherapy. Initial chemotherapy consisted of chlorambucil in 15, oral etoposide in 2, and combination protocol in 62. Only 16% of patients received full-dose therapy, and only 50% completed ≥6 cycles of combination chemotherapy. The overall response rate for the 69 evaluable patients was 84% (complete 56.5%, partial 27.5%). Overall 5-year survival for the whole group was 39%, and median survival time was 26 months. ConclusionA high response rate can be achieved in very elderly NHL patients despite aggressive histology, poor prognostic features, and reduced doses of chemotherapy. Age alone should not be a contraindication to treatment.

Combination Antibody Therapy With Epratuzumab and Rituximab in Relapsed or Refractory Non-Hodgkin's Lymphoma

To explore the safety and therapeutic activity of combination anti-B-cell monoclonal antibody therapy in non-Hodgkin's lymphoma (NHL). Twenty-three patients with recurrent B-cell lymphoma received anti-CD22 epratuzumab 360 mg/m(2) and anti-CD20 rituximab 375 mg/m(2) monoclonal antibodies weekly for four doses each. Sixteen patients had indolent histologies (15 with follicular lymphoma) and seven had aggressive NHL (all diffuse large B-cell lymphoma [DLBCL]). Indolent patients had received a median of one (range, one to six) prior treatment, with 31% refractory to their last therapy and 81% with high-risk Follicular Lymphoma International Prognostic Index scores. Patients with DLBCL had a median of three (range, one to eight) prior regimens (14% resistant to last treatment) and 71% had high intermediate-risk or high-risk International Prognostic Index scores. All patients were rituximab naïve. Treatment was well tolerated, with toxicities principally infusion-related and predominantly grade 1 or 2. Ten (67%) patients with follicular NHL achieved an objective response (OR), including nine of 15 (60%) with complete responses (CRs and unconfirmed CRs). Four of six assessable patients (67%) with DLBCL achieved an OR, including three (50%) CRs. Median time to progression for all indolent NHL patients was 17.8 months. The full-dose combination of epratuzumab with rituximab was well tolerated and had significant clinical activity in NHL, suggesting that this combination should be tested in comparison with single-agent treatment.

CD10 and Bcl‐2 expression combined with the International Prognostic Index can identify subgroups of patients with diffuse large‐cell lymphoma with very good or very poor prognoses

Diffuse large B-cell lymphoma (DLBCL) is characterized by marked biological heterogeneity. The identification of reproducible parameters that can be combined with the International Prognostic Index (IPI) to better predict outcome could lead to the development of effective risk-adaptive strategies. Bcl-2 and CD10 expression was determined by immunohistochemistry. The impact of the positivity on survival was evaluated in combination with the IPI in 86 patients with a confirmed diagnosis of DLBCL. Patients were divided according to the IPI into low-risk (no to two factors) or high-risk (three to five factors) groups. Positivity rates were 25% for CD10 and 42% for Bcl-2. In a Cox analysis, the high-risk IPI group [hazard ratio (HR) 5.98, P < 0.0001) and Bcl-2 expression (HR 2.43, P = 0.02) were independent poor prognostic factors, and expression of CD10 (HR 0.41, P = 0.052) predicted a favourable outcome. Among patients in the low-risk IPI group, CD10 positivity was associated with an excellent 8-year overall survival (92% versus 45%, P = 0.06). In the high-risk IPI group, Bcl-2 positivity identified a subgroup with invariably fatal disease. The expression of CD10 in the low-risk IPI group, and the expression of Bcl-2 in the high-risk IPI group can identify two subgroups of patients who might benefit from new risk-adaptive treatment approaches.

Venous Thromboembolic Events in Patients with Diffuse Large B cell Non- Hodgkin's Lymphoma.

Background:Venous thromboembolism (VTE) including deep venous thrombosis (DVT) and pulmonary embolism (PE) is a well-known complication of cancer. VTE frequency varies according to the underlying malignancy. Diffuse large B cell Lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma (NHL). VTE during initial treatment of DLBCL is a complication recognized by treating physicians. Little information is available regarding the frequency of VTE and its association with outcomes in DLBCL. We conducted a retrospective cohort study to determine the frequency and timing of VTE during initial treatment of DLBCL, as well as identifying risk factors associated with VTE, and the clinical impact of VTE on survival.Methods:We reviewed records of consecutive patients diagnosed with de novo DLBCL seen at University of Rochester from January 1990 to December 2001. Patients with transformed DLBCL, CNS lymphoma, HIV-related NHL, and patients whose complete records were unavailable were excluded. We considered only episodes of VTE that occurred during the initial treatment of DLBCL. For analysis of risk factors for VTE, Chi-square test or Fisher's exact test was used to compare the categorical variables and t-test was used to compare continuous variables. Kaplan-Meier estimate was used to compare overall survival between patients with or without VTE. Log-rank test was used to compare statistical differences between survival curves.Results:A total of 211 patients with DLBCL were included. VTE occurred in 27 patients (12.8%). DVT occurred in 22, PE occurred in 3, and both DVT and PE in 2. Of all VTE, 37% occurred at diagnosis of DLBCL, and 82% in the first three cycles of treatment. VTE involved the lower limb in 44%. Baseline characteristics were similar between patients with or without VTE regarding age, sex, race, ECOG performance status, histology, B symptoms, LDH, and bone marrow involvement. Fewer patients with VTE, however, were stage I compared to the no VTE group (3.7% vs 27.3 %, P = 0.017). Furthermore, patients with VTE were more likely to be in the high-risk international prognostic index (IPI) category (29.6% vs 10.3%, P = 0.048). Median survival time for patients with VTE was 1.04 years (95% CI 0.75–1.33) compared to 5.2 years for patients with no VTE (95% CI 1.8–8.6) (Log rank test, P = 0.038). [Display omitted] Conclusion:VTE is a frequent complication of initial treatment of DLBCL. The majority of cases occur at diagnosis or during the first three cycles of treatment. High-risk IPI is associated with increased incidence of VTE during initial treatment of DLBCL. VTE is a poor prognostic factor and is associated with inferior survival. Clinical trials of thromboprophylaxis are warranted.

The MYOCAN Study. A Phase II Study of Cyclophosphamide, Oncovin, Myocet™, and Prednisone Plus Rituximab (R-COMP) in the Treatment of Elderly Patients with Diffuse Large B-Cell Non-Hodgkin Lymphoma (DLBCL).

BACKGROUND: For more than 20 years, CHOP has been the gold standard treatment for patients with aggressive NHL. The addition of rituximab to this regimen has been shown to improve outcomes in elderly patients with advanced (Coiffier et al NEJM 2002; 346:235–42). However, CHOP is often poorly tolerated by elderly patients resulting in dose reductions and consequently lower response and cure rates compared to younger patients. Myocet™ (non-pegylated liposomal doxorubicin) has an improved pharmacokinetic profile with less myelosuppression and GI toxicity and has a reduced risk of cardiotoxicity at dose levels equivalent to standard formulations of doxorubicin.METHODS: In this phase II, open label, 2-stage study, we replaced the conventional doxorubicin with Myocet™ to evaluate the response rate and safety of the R-COMP regimen (rituximab, cyclophosphamide, vincristine, Myocet™, prednisone). Previously untreated, elderly patients (≥60 yrs) with CD20+ newly diagnosed, advanced DLBCL were treated every 3 weeks with: Myocet™ 50mg/m2, cyclophosphamide 750mg/m2, vincristine 1.4 mg/m2 (max. 2mg), rituximab 375 mg/m2 (day 3 on cycle 1, day 1 thereafter) and prednisone 100mg/d d1–5 for 8 cycles. Response was assessed after 3 and 8 cycles.RESULTS: Thirty patients were enrolled in stage 1 of the study with a median age of 72 (range 61–82). At baseline 17 (56%) patients had stage III–IV disease; 60% had an intermediate or high risk (2+) International Prognostic Index score and the median LVEF was 59% (range 50–75). A total of 198 cycles of chemotherapy were given, with a median of 8 cycles (range 1–8). Of the 198 cycles administered 15 (8%) were delayed by haematological or hepatic toxicity for a median of 7 days (range 0 to 25). The relative dose intensity for the regimen was 87%, for Myocet™ it was 84%. Toxicity was mainly haematological with grade 3 or 4 neutropenia in 29% of cycles and febrile neutropenia in 4%. There was no grade 3 or 4 vomiting and a low incidence of grade 1 or 2 vomiting (3%). At the last observation the median LVEF was 55% (range 40–76), 16 patients had no change or an improved LVEF and 13 patients had a reduced LVEF. In the cohort of 24 patients evaluable for response, 15 (63%) had a complete response and an additional 7 (29%) achieved a partial response.CONCLUSIONS: These interim results suggest R-COMP is a well tolerated regimen with promising response rates in elderly patients with advanced DLBCL. Patient recruitment continues in stage 2 of the study with the aim of enrolling a total of 75 patients with a 2-year follow-up.

Response to Tositumomab and Iodine 131I-Tositumomab (BEXXAR) Based on International Prognostic Index (IPI) Score.

Purpose: The therapeutic efficacy of Bexaar (tositumomab and131I tositumomab) in the treatment of follicular lymphoma patients who have relapsed or had refractory disease after rituximab has been demonstrated. A retrospective review has reported durable complete responses in patients who were both rituximab refractory and naive.1 Results of an expanded access program reported a 59% overall response rate with a median duration of 15 months in patients with relapsed or refractory NHL.2 We report results on 33 patients treated in the expanded access program and have attempted to identify patient characteristics predictive of response or outcome.Methods: From April 1999 to November 2001, 33 patients with refractory NHL were enrolled in an IRB-approved expanded access trial at Tufts New England Medical Center. Patients were dosed with 450 mg of tositumomab and a total body exposure of 75cGy with 131I-tositumomab.Results: Of 33 treated patients, 24 had follicular lymphoma, 6 had transformed to diffuse large cell lymphoma, and 3 had small lymphocytic lymphoma. Median prior therapies was 2 (range 1–6), with 18 rituximab refractory and 15 rituximab naïve. Of 33 evaluable patients, the overall response rate was 67%, with 59% (13/22) of responders achieving CR. Median progression free survival (PFS) of the responders was 19 months, compared to a median PFS of 4 months with their last therapy. Median overall survival was 44 months in the 22 responders compared to 23 months in non-responders (p=.002). Among all patients, 28 of 33 eventually developed progressive disease, and 17 deaths had occurred during this study period. Median time to ANC nadir was 41 days and PLT nadir occurred at a median of 34 days. Two patients developed AML/MDS, and no patient required long term treatment for thyroid dysfunction. When prognostic factors were considered, 15 patients had an International Prognostic Index (IPI) score of 4–5. The median survival in this group was 24 months, while patients with Intermediate risk IPI scores of 2–3 (18 pts) had not yet reached median survival at 42+ months. Duration of response was 12 months in the high-risk IPI group compared to 42 months in the intermediate-risk group (p=.0017). Prior rituximab was also an independent predictor of outcome, with a median response duration of 12 months in rituximab exposed vs 38 months in rituximab naïve patients (p=.03), although there was not a statistically significant difference in response rates between the two groups. Because or number of transformed patients was small, it was impossible to correlate response based on histology.Conclusions: We report an overall response rate of 67% with a response duration of 19 months in responders. Median overall survival for responders was in excess of 44 months. Response duration was higher for patients with low -intermediate IPI scores and in rituximab naïve patients. A response duration of 12 months in the high IPI group in this retrospective analysis suggests that Bexaar therapy may be associated with an improved outcome compared to other therapies. Further prospective studies stratifying patients based on IPI score are underway.

Standard CHOP therapy for low (L) or low-intermediate (L-I) risk patients (pts) with aggressive non-Hodgkin's lymphoma (NHL): A multicenter phase II study by Japan Clinical Oncology Group (JCOG 9508)

6703 Background: To confirm the efficacy and safety of standard CHOP therapy in Japanese pts with L or L-I risk aggressive NHL, we conducted a multicenter phase II study with overall survival (OS) as primary endpoint. Methods: Eligibility criteria were as follows: newly-diagnosed, intermediate or high grade NHL by Working Formulation; L or L-I risk by International Prognostic Index (IPI); clinical stage of II, III, IV or bulky I; ages less than 70; PS 0–3. Eight courses of standard CHOP therapy were given every 3 weeks. Involved-field radiotherapy (30 to 40 Gy) was added after chemotherapy for bulky disease at baseline, and was optional for residual tumors. Results: Between June 1995 and May 1999, a total of 213 pts were enrolled, and 173 pts were pathologically eligible (diffuse large B; 68%) by the central review according to WHO classification. Out of 173 pts, 87 and 80 pts were of L and L-I risk, respectively. Three pts with high-intermediate IPI risk, 1 high IPI risk, 1 stage I without bulky disease, and 1 prior radiotherapy were ineligible. % complete response of L and L-I risk pts was 83% (95% CI; 74–90%) and 74% (95% CI; 63–83%), respectively. Five-year OS was 73% (95% CI; 64–83%) and 64% (95% CI; 53–74%), and 5-year progression-free survival (PFS) was 63% (95% CI; 52–73%) and 38% (95% CI; 27–59%). Major toxicity by JCOG toxicity criteria in all treated pts (212 pts) was grade 4 neutropenia (64%). Non-hematologic toxicities were acceptable; the most frequent grade 3 toxicity was nausea/vomiting (3%), and grade 4 toxicity was observed in one who developed paralytic ileus. One treatment-related death was observed due to hepatitis B virus reactivation. Conclusions: CHOP was confirmed to be a standard therapy in Japanese pts with L or L-I risk aggressive NHL. However, the relatively low %PFS suggests the necessity of further investigations to find more effective first-line therapy for L-I risk pts. No significant financial relationships to disclose.