Diffuse Large Cell Lymphoma Patients Research Articles

PROSPECTIVE STUDY OF 3T WHOLE BODY DIFFUSION WEIGHTED MAGNETIC RESONANCE (WB DWI MRI) COMPARED TO PET IN STAGING AND ASSESSMENT OF TREATMENT RESPONSE IN FDG AVID LYMPHOMAS

Introduction: PET is considered the gold standard for staging and evaluation of treatment response in FDG avid Lymphoma. 3T WB-DWI-MRI may represent an option for detection and better characterisation of tumoral lesions without use of FDG or iodated/paramagnetic contrast medium. We compared 3T WB-DWI-MRI with PET in the evaluation of Hodgkin lymphoma (HL) and Diffuse large cell lymphoma patients (DLBCL). Methods: From may 2016, 25 patients (14 cases of HL and 11 cases of DLBCL) were diagnosed at our institution. PET and 3T WB-DWI-MRI was perfomed at diagnosis and post treatment for a total of 118 nodal sites and 21 extranodal valued sites. DWI imaging was obtained with multi shot sequences (thickness 4 mm) multi-b (b-value: 0, 150, 1000) and ADC cut off value 1.2 for functional evaluation. Morphological images were obtained by using sequences fast spin-echo short time inversion recovery (STIR with thickness 4mm) and Turbo spin-echo (T2-TSE with thickness 4mm) and sequnces T1-FAST-Field-echo (T1-FFE) in and out - phase (thickness 4mm). MRI were compared with PET imaging performed at the same time and assessed blind by radiologist and Nuclear Medicine physician. Results: The 3T WB-DWI-MRI and PET results were concordant at the diagnosis after evaluation of 118 nodal site and 21 extra nodal site with Cohen's Kappa coefficient showed agreement to be excellent (K = 0.82 and 0.84 respectively). When performed after treatment the two methods were not concordant due to the greater sensitivity and specificity of the RMI (high positive and negative predictive value. In 5/25 cases of nodal site and in 2/16 cases of extra nodal site after chemotherapy MRI and PET results were discordant and PET failed complete remission finding (doubts residues after therapy not confirmed at subsequent follow-up). Conclusions: These data suggest that 3T WB-DWI-MRI can be considered a sensitive and specific method for assessing treatment response in Lymphoma without the use of ionising radiation or administration of F-18 Flurodeoxyglucose. In this population, MRI appears to obtain a better definition of the response after chemotherapy especially in mediastinal, hepatic, waldeyer ring and bone sites. Further studies are needed to evaluate the optimum ADC values in assessing treatment response in a more large number of patients. Keywords: diffuse large B-cell lymphoma (DLBCL); Hodgkin lymphoma (HL); positron emission tomography (PET).

Interim and Post-Treatment Positron Emission Tomography-Computed Tomography Scan Status Is Highly Predictive Of Outcome In Diffuse Large Cell Lymphoma Patients Treated With R-CHOP21

BackgroundTaking a step forward from the international prognostic index, attention is focused on the role of 18F-fluorodeoxyglucose positron-emission tomography-Computed Tomography scan (PET) as a tool for guidance in risk stratification in patients with diffuse large B-cell lymphoma (DLBCL). Here, we analyzed the predictive value of interim and post-treatment PET in patients with DLBCL. MethodsIn our retrospective study, we analyzed a homogeneous cohort of newly diagnosed DLBCL patients treated with R-CHOP21 who underwent PET scan at diagnosis, after three cycles of chemotherapy and at the end of treatment. For interim PET, images were interpreted by computing maximum standardized uptake value between PET performed at baseline and after three cycles of immuno-chemotherapy (¦¤SUVmax). The images of post-treatment PET were interpreted visually according to the International Harmonization Project criteria. The primary study endpoints were progression-free survival (PFS) and overall survival (OS). ResultsThirty-eight patients with DLBCL with PET data were identified. The median follow-up was 28 months. At interim PET evaluation, optimal cutoff to predict progression was 66% for ¦¤SUVmax. ¦¤SUVmax analysis (≥66% vs< 66%) identified patients with significantly different 2-year PFS (90.7% vs 38.9%; P =.000) and 2-year OS (95.5% vs 62%; P=.016) (Fig1). Post-treatment PET status (negative vs positive) was statistically significantly associated with 2-year PFS (91% vs 45.5%; P =.001) and 2-year OS (100% vs 72.7%; P =.012) (Fig2). [Display omitted] [Display omitted] ConclusionsThese data support the prognostic utility of PET in interim and post-treatment settings in patients with DLBCL treated with R-CHOP21. An interim PET scan after three cycles of treatment can effectively predict the outcome by using quantitative assessment of ¦¤SUVmax and allows clinicians to design a risk-adapted therapeutic strategy. A positive PET after the completion of therapy identifies a patient subset with an inferior PFS and OS. Disclosures:No relevant conflicts of interest to declare.

Comparative Analysis of Autologous Hematopoietic Cell Transplantation with Radioimmunotherapy (RIT) Based Conditioning Versus Total Body Irradiation (TBI) for High-Risk Diffuse Large Cell Lymphoma (DLCL): Toxicity and Efficacy

AbstractAbstract 32 Background:RIT based conditioning offers the potential of combining the efficacy of radiation with decreased toxicity over traditional TBI. In pilot trials we demonstrated that combining Yttrium 90 (ibritumomab tiuxetan) with high-dose BEAM (ZBEAM) is feasible and has a toxicity profile similar to high-dose BEAM. Herein we report the results of a comparative analysis designed to evaluate transplant outcomes among DLCL patients who were conditioned with either ZBEAM or a TBI-based conditioning regimen. Patients were matched on age (+/− 5 years), disease status, number of prior regimens, year of diagnosis (+/− 5 years), and year of transplant (+/− 5 years). There was a total of 92 DLCL patients treated from 01/1997-01/2009; 46 patients in each treatment group. The median patient age was 56.5 years (range: 19–78) for the ZBEAM group, and 53 years (range: 21–62) for the TBI group. Both groups had a median of two prior regimens, with 13% (ZBEAM) and 15% (TBI) considered high-risk first remission, 65% beyond 1st CR and 22% induction failures in each cohort. The median length of follow-up for surviving patients was 51–83 months. There was a trend toward improved PFS in the RIT group: 2 year PFS for ZBEAM group 66% (95%CI: 56–74) vs. 50% (95%CI: 43–57) for TBI group (p<0.08). Results to date show that a plateau in PFS appears to have been achieved for both groups (at 2.6 years in the ZBEAM group and 3.7 years for the TBI group), which translates into a 20% improvement in PFS for the ZBEAM patients, >4 years post transplant. Similarly the OS estimate was significantly higher for ZBEAM compared to TBI controls: 84% vs. 59 % (p<0.01). The lower OS rate for the TBI cohort was primarily due to toxicity, with a 2 year non relapse mortality of 0% for ZBEAM vs. 13% for TBI. (p<0.01) The causes of death included: relapse progression n=9 (ZBEAM), n=15 (TBI), infection n=2 TBI, cardiac disease n=2 TBI, pneumonia N= 1 TBI, unknown N=3 TBI. Conclusions:RIT based conditioning demonstrated improved survival when compared to traditional radiation based regimens in the treatment of DLCL due to a more favorable toxicity profile, while maintaining potent anti-lymphoma effects. [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Early Evidence of Anti-Lymphoma Activity of the Cyclin Dependent Kinase Inhibitor Dinaciclib (SCH 727965) In Heavily Pre-Treated Low Grade Lymphoma and Diffuse Large Cell Lymphoma Patients

AbstractAbstract 3966 Background:Dinaciclib (SCH 727965) is a potent and selective inhibitor of the cyclin dependent kinases CDKs 1, 2, 5, and 9, with in vitro activity against lymphoma. Methods:A phase 1 trial of dinaciclib administered by 2-hour i.v. infusion on days 1, 8 and 15 of a 28-day cycle was undertaken in solid tumor patients with 12 mg/m2 established as the recommended phase 2 dose (RPTD). The RPTD was explored in expansion cohorts of up to 10 patients each with low grade lymphomas (primarily follicular lymphoma (FL)), and intermediate/high grade lymphomas (diffuse large B-cell lymphoma (DLBCL)). Sixteen patients have been treated with dinaciclib, including 7 with FL, 1 with mantle cell lymphoma (MCL) and 1 with marginal zone lymphoma (MZL) in the low grade group and 7 with DLBCL in the intermediate/high grade group. Patient median age was 66 (range 43–82) and the median number of prior therapies was 2.5 (range 1–8). All patients received prior rituximab and 4 patients had previously received flavopiridol. All patients were treated with dinaciclib at the 12 mg/m2 dose. Dose de-escalation to 10 mg/m2 was required in 2 patients during treatment. The median number of cycles administered was 3 (range 1–9) with 3 patients continuing treatment for 3 cycles, 4 for 6 cycles, and 1 for 9 cycles. Of the 16 lymphoma patients treated, 2 remain on treatment. Response:Responses were assessed using the revised Cheson criteria for lymphoma (J Clin Oncol 25: 579-86, 2007). One partial response in a patient with DLBCL was observed with an 85% decrease in tumor mass. This patient, previously treated with R-CHOP from May-August 2008 and R-ICE from December 2008-March 2009, was able to continue on to autologous stem cell transplantation for potential curative salvage. Activity not meeting criteria for partial response was seen in 2 patients with FL (decreased tumor mass of 27% and 39%, respectively) and one patient with MCL (8% decrease in tumor mass). Toxicity:Treatment-related adverse events occurring in ≥ 25% of pts included anemia, cytokine release syndrome, nausea, vomiting, diarrhea, fatigue, leucopenia, lymphopenia, neutropenia, and thrombocytopenia. The most common CTCAE v3.0 treatment-related grade 3 and 4 toxicities, occurring in 3 or more patients, were leukopenia, lymphopenia, and neutropenia. Cytokine release syndrome was observed in 4 patients, was manageable with dexamethasone and did not prevent continued treatment on protocol. Conclusion:Dinaciclib demonstrates clinical responses in heavily pre-treated lymphoma patients supporting further study in lymphoma and other hematologic malignancies. Updated information with longer follow-up will be presented. Disclosures:Off Label Use: SCH 727965 is an investigational drug. Small:Merck & Co.: Employment, Equity Ownership. Statkevich:Merck & Co.: Employment, Equity Ownership. Bannerji:Merck & Co: Employment, Equity Ownership.

A comprehensive geriatric assessment is more effective than clinical judgment to identify elderly diffuse large cell lymphoma patients who benefit from aggressive therapy

The authors set out to analyze if a simple comprehensive geriatric assessment (CGA) could objectively identify elderly patients with diffuse large cell lymphoma (DLCL) who can be effectively treated with anthracycline-containing immunochemotherapy. CGA was performed in 84 consecutive patients with DLCL aged >65 years and diagnosed at a single institution. Treatment with curative versus palliative intent was chosen according to clinical judgment. Cyclophosphamide, hydroxydaunomycin, Oncovin (vincristine), and prednisone (CHOP) or CHOP-like regimens were given to 62 (74%) patients. The outcome of patients was analyzed according to both the treatment received and the results of CGA. According to CGA, 42 (50%) patients were classified as "fit." They were younger (P < .0001) and had less frequent systemic symptoms (P = .03). These patients received curative treatment by clinical judgment. Their response rate (92.5% vs 48.8%; P < .0001) and median survival (not reached vs 8 months; P < .0001) were significantly better than those of 42 patients considered "unfit" by CGA. Among unfit patients, 20 had actually received curative and 22 palliative therapy. These subgroups did not differ in any geriatric or lymphoma-related characteristic. Their outcome was similar irrespectively of the type of treatment received (median survival, 8 vs 7 months; P = nonsignificant). Lymphoma rather than toxicity was the main cause of failure/death also among unfit patients treated aggressively. CGA is an efficient method to identify elderly DLCL patients who can benefit from a curative approach with anthracycline-containing immunochemotherapy. Further study is needed to discern why unfit patients seem to have poor outcomes because of poor tolerance but also because of lymphoma refractoriness to intensive therapy.

Promoter Methylation of Multiple Genes in Diffuse Large Cell Lymphoma (DLCL), Follicular Lymphoma (FL) and Bening Follicular Hyperplasia (BFH).

Transcriptional silencing of tumor suppressor genes, associated with DNA methylation, is a common epigenetic event in leukemias and myelodisplastic syndromes. Much less is known about the specific methylation changes that occur in DCLC, FL and their normal counterpart BFH. Methylation of cyclin dependent kinase inhibitors is more common in high grade lymphomas and may be an important step in the progression and transformation of follicular lymphoma. We determined the methylation status of 7 tumor suppressor genes in 31 patients with B-cell malignancies. Seven patients with benign follicular hyperplasia were used as normal controls. The target genes chosen are potentially involved in B-cells malignancies and encoding proteins implicated in apoptosis regulation (death associated protein kinase, DAP-K), Jak/STAT3 signalling pathway (SHP1), hormonal response (RARb), DNA repair (O6-methilguanine-DNA methyltranferase, MGMT), cell cycle control (p14ARF and p15INK4b) and detoxification of environmental xenobiotics such as doxorubicin (glutathione S-transferase P1, GSTP1). Genomic DNA extracted from paraffin-embedded samples of thirty one B-cell malignancies (twenty six DLCL and five FL) were analyzed by methylation-specific polymerase chain reaction to determine promoter hypermethylation of DAP-k, SHP1, Rarβ, MGMT, p14, p15 and GSTP1. Samples were obtained mostly from lymph nodes; spleen, stomach, skin, and parathyroid gland biopsies were also included. Specimens were collected at diagnosis before specific therapy. Diagnosis was based on morphology and immunohistochemistry analysis. All cases were matched for age, sex and ethnic origin. DAP-k promoter methylation occurred with similar frequency in DLCL (100%), FL (100%) and BFH (86%). SHP1 was methylated in 75% of DLCL, all FL and the 7 patients with BFH. RARb was methylated in all DLCL and FL patients and 85% of the BFH. Sixteen (50%) DLCL, three (60%) FL and none BFH patients showed MGMT methylation. Promoter hypermethylation of p14 and p15 was detected in 11 (42%) and 13 (50%) DLCL, 2 (40%) and 3(60%) FL, 3(42%) and 5(71%) BFH patients respectively. Methylation of GSTP1 was absent in all samples. Inactivacion of DAP-K, SHP1 and Rarβ is present in B-cell malignancies, DLCL and FL, and BFH. Therefore, it may represent a physiologic event conferring a temporal survival advantage necessary for a BFH response. With our data methylation of Cyclin dependent kinase inhibitors such as p14 and p15 is not a differential pathogenic event in DLCL with respect to FL or BFH. Finally, the absence of GSTP1 methylation in DLCL and FL questions its relevance in B-cell neoplasia development.

Predictive value for survival of a risk model of two serological markers, beta-2-microglobulin (B2M) and lactic dehydrogenase (LDH), in diffuse large cell lymphoma (DLCL)

10599 Background: The International Prognostic Index (IPI), the standard tumor risk model in patients (pts) with diffuse large cell lymphoma (DLCL), has 5 factors (age, LDH, performance status, extra nodal sites, and stage). We previously proposed a simpler two-factor model, based on LDH and B2M (JCO10;1989). B2M is a component of HLA class I antigens, expressed in lymphocytes, and a known prognostic indicator in some lymphoid malignancies. The benefits of this model are: objective measures; lab method widely available; simplicity; biologic marker. Methods: We applied the model to a large cohort of DLCL patients with prospective baseline B2M, and treated with doxorubicin-based (chemo) regimens, with and without rituximab. 718 pts with DLCL were sequentially treated at MDACC by IRB approved chemo protocols from 1988–2000. In 2001, rituximab plus chemo (RCHOP) became standard. 311 DLCL pts were sequentially treated with RCHOP from 2001–2005. Cox regression analyses for univariate and multivariate models of IPI factors and B2M were done. Kaplan-Meier survival projections were in three risk categories: low (normal [nl] LDH and B2M); intermediate (either LDH or B2M &gt; nl); or high (LDH and B2M &gt; nl). Results: In both treatment groups, IPI factors and B2M were significant as univariate factors. In the RCHOP group, however, the IPI multivariate model showed age, stage, and extra-nodal sites were not significant risk factors, while B2M and LDH remained highly significant (p&lt;0.01). The 5 year survival projections by risk category were: (*) combines intermediate low and intermediate-high categories Conclusions: This simple two-factor model predicts risk for patients with DLCL, treated with or without rituximab, comparably to the IPI. B2M should be considered an important prognostic indicator in DLCL, particularly in rituximab treated patients. Exploratory analyses to revise the IPI model are indicated. [Table: see text] No significant financial relationships to disclose.

Association Between Hepatitis C Virus and Non-Hodgkin's Lymphomas

TO THE EDITOR: In the February 20, 2006, issue of the Journal of Clinical Oncology, Besson et al reported that the Groupe d Etude des Lymphomes de l Adulte found differences in clinical presentation and worsened prognosis in 26 patients with diffuse large-cell lymphoma (DLCL) and hepatitis C virus infection (HCV) compared with DLCL HCV-negative patients. Only patients who were included in the clinical trial were studied and the prevalence in the population selected was 0.5%. Our group examined 114 patients with non-Hodgkin’s lymphoma who were not selected, except for the exclusion of patients who were seropositive against the AIDS virus and parenteral drug addicts. We detected 15 HCV positives (13%). We did not find significant differences in relation to the presence or absence of HCV infection in the clinical presentation, nor did we find any association between highor low-malignancy grade. We did find a significant difference in global survival between the eight DLCL patients who were HCV positive (75% at 2 years; 95% CI, 45% to 100%) and the 50 DLCL patients who were HCV negative (94% at 2 years; 95% CI, 87% to 100%; P .022). We found no relation between HCV infection and survival in the rest of the patients grouped as low-grade lymphomas. In our experience the percentage of HCV infection is similar in highand low-grade lymphomas, and prognosis is no worse in the latter. We found a greater prevalence of HCV infection and lymphomas than that reported for the selected population studied by Groupe d Etude des Lymphomes de l Adulte.

Does Follicularity in Large Cell Lymphoma Predict Outcome after Autologous Stem Cell Transplantation?

The purpose of this study was to evaluate whether follicular histology in large cell lymphoma influences treatment outcomes after autologous stem cell transplantation (ASCT). It remains an area of controversy whether the natural history of follicular large cell lymphoma (FLCL) is akin to diffuse large cell lymphoma (DLCL) with curative potential or is more similar to indolent follicular lymphomas with a pattern of late relapses after intensive chemotherapy. Although ASCT is a potentially curative treatment for patients with recurrent DLCL, the effectiveness of this approach in patients with FLCL is unclear. We undertook a retrospective analysis of 332 patients with large cell lymphoma who underwent ASCT at the City of Hope Comprehensive Cancer Center. With a median follow-up of 31 months, the projected 10-year overall survival and disease-free survival were similar between patients with FLCL and DLCL. Analysis of prognostic factors demonstrated that although age, chemotherapy refractoriness, and disease status at the time of ASCT were predictive of overall survival/disease-free survival, follicularity did not influence the outcome. Furthermore, the similar plateau in the survival curve for the DLCL and FLCL patients suggests that the behavior of FLCL is similar to that of DLCL and that FLCL is potentially curable with ASCT.

The prognostic impact of bone marrow involvement in patients with diffuse large cell lymphoma varies according to the degree of infiltration and presence of discordant marrow involvement

The prognostic significance of marrow involvement in diffuse large cell lymphoma (DLCL) is controversial. Factors that that have been reported to influence prognosis include the pattern and extent of marrow infiltration and histological discordance between the primary site and the bone marrow. Bone marrow biopsies from 172 patients with newly diagnosed DLCL entered in two consecutive trials of the Australasian Leukaemia and Lymphoma Group were analyzed. Progression-free (PFS) and overall survival (OS) were calculated according to the absence or presence of bone marrow involvement (BMI), the extent of lymphomatous infiltration and the presence of histological discordance between the primary site and the bone marrow. Of 172 patients with DLCL accrued between 1982 and 1990, who were treated with CHOP or CHOP-like regimens, 47 (27%) demonstrated marrow involvement on examination of multiple levels. Seventy two percent (34/47) of patients had discordant marrow involvement (<50% large cells) and 28 had minimal (<10%) involvement; these latter patients with minimal marrow involvement (<10%) had similar PFS & OS to the 113 patients without involvement. Within the group of 47 patients with marrow involvement, an increasing percentage of BM involvement was significantly associated with an increasing percentage of concordant histology and a decreasing PFS & OS. Minimal BMI, seen in the majority of patients with DLCL with marrow infiltration, appears not to influence the PFS & OS. However, an increasing degree of marrow involvement is associated with an increasing component of large cells and a poorer prognosis in DLCL patients, independent of other risk factors.

Crystal Structures of Proto-oncogene Kinase Pim1: A Target of Aberrant Somatic Hypermutations in Diffuse Large Cell Lymphoma

Pim1, a serine/threonine kinase, is involved in several biological functions including cell survival, proliferation, and differentiation. While pim1 has been shown to be involved in several hematopoietic cancers, it was also recently identified as a target of aberrant somatic hypermutation in diffuse large cell lymphoma (DLCL), the most common form of non-Hodgkin's lymphoma. The crystal structures of Pim1 in apo form and bound with AMPPNP have been solved and several unique features of Pim1 were identified, including the presence of an extra beta-hairpin in the N-terminal lobe and an unusual conformation of the hinge connecting the two lobes of the enzyme. While the apo Pim1 structure is nearly identical with that reported recently, the structure of AMPPNP bound to Pim1 is significantly different. Pim1 is unique among protein kinases due to the presence of a proline residue at position 123 that precludes the formation of the canonical second hydrogen bond between the hinge backbone and the adenine moiety of ATP. One crystal structure reported here shows that changing P123 to methionine, a common residue that offers the backbone hydrogen bond to ATP, does not restore the ATP binding pocket of Pim1 to that of a typical kinase. These unique structural features in Pim1 result in novel binding modes of AMP and a known kinase inhibitor scaffold, as shown by co-crystallography. In addition, the kinase activities of five Pim1 mutants identified in DLCL patients have been determined. In each case, the observed effects on kinase activity are consistent with the predicted consequences of the mutation on the Pim1 structure. Finally, 70 co-crystal structures of low molecular mass, low-affinity compounds with Pim1 have been solved in order to identify novel chemical classes as potential Pim1 inhibitors. Based on the structural information, opportunities for optimization of one specific example are discussed.

Prognostic value of soluble MUC1 and anti-MUC1 antibody levels in patients with diffuse large B-cell lymphoma

6586 Background: A soluble form of mucin MUC1 (sMUC1) as well as antibodies anti-MUC1 can be found in peripheral blood (PB) of patients with MUC1+ carcinoma or myeloma. MUC1 is expressed in 80% of diffuse large cell lymphoma (DLCL). Methods: sMUC1 level was evaluated in 80 VBD (Volunteer Blood Donor) and 95 DLCL pts using an immunoassay that detects the MUC1 CA27.29 epitope. All DLCL pts were treated on study with the same anthracyclins-containing regimen at MD Anderson between 1993 and 1996. IgM and IgG antibodies against MUC1 were quantified using an immunoassay with a 60aa peptide part of MUC1 tandem repeat. The median level of sMUC1, anti-MUC1-IgG and anti-MUC1-IgM found in VBD was used as a cutoff to separate the patients in two groups. Results: The sMUC1 level was significantly higher in DLCL (mean 25.4 ± 11.3 U/ml) than in VBD (mean value 15.6 ± 9.1 U/ml) (p < .0001, Mann-Whitney). The level of circulating anti-MUC1-IgG was also significantly higher in DLCL (1.211 ± 0.959 Arb, U/ml) than in VBD (1.015 ± 0.667 Arb, U/ml) (p=. 0041, Mann-Whitney), but not for anti-MUC1-IgM. There was no statistical correlation between the levels of sMUC1 and the presence of anti-MUC1 antibodies. The 10-year failure-free survival (FFS) was 87.1% for pts with low sMUC1 vs. 56.7% for pts with high sMUC1 (p = .026; log-rank test.). The same correlation was seen with overall survival (P < .05). In addition sMUC1 remained an independent prognostic variable for FFS. The level of circulating anti-MUC1-IgG or anti-MUC1-IgM did not correlate with either FFS or OS. Conclusions: A high level of circulating of sMUC1 is associated with a poor outcome in patients with DLCL. The level of circulating anti-MUC1 antibody was not found predictive of survival in DLCL patients in our study. No significant financial relationships to disclose.

Prognostic value of soluble MUC1 and anti-MUC1 antibody levels in patients with diffuse large B-cell lymphoma

6586 Background: A soluble form of mucin MUC1 (sMUC1) as well as antibodies anti-MUC1 can be found in peripheral blood (PB) of patients with MUC1+ carcinoma or myeloma. MUC1 is expressed in 80% of diffuse large cell lymphoma (DLCL). Methods: sMUC1 level was evaluated in 80 VBD (Volunteer Blood Donor) and 95 DLCL pts using an immunoassay that detects the MUC1 CA27.29 epitope. All DLCL pts were treated on study with the same anthracyclins-containing regimen at MD Anderson between 1993 and 1996. IgM and IgG antibodies against MUC1 were quantified using an immunoassay with a 60aa peptide part of MUC1 tandem repeat. The median level of sMUC1, anti-MUC1-IgG and anti-MUC1-IgM found in VBD was used as a cutoff to separate the patients in two groups. Results: The sMUC1 level was significantly higher in DLCL (mean 25.4 ± 11.3 U/ml) than in VBD (mean value 15.6 ± 9.1 U/ml) (p < .0001, Mann-Whitney). The level of circulating anti-MUC1-IgG was also significantly higher in DLCL (1.211 ± 0.959 Arb, U/ml) than in VBD (1.015 ± 0.667 Arb, U/ml) (p=. 0041, Mann-Whitney), but not for anti-MUC1-IgM. There was no statistical correlation between the levels of sMUC1 and the presence of anti-MUC1 antibodies. The 10-year failure-free survival (FFS) was 87.1% for pts with low sMUC1 vs. 56.7% for pts with high sMUC1 (p = .026; log-rank test.). The same correlation was seen with overall survival (P < .05). In addition sMUC1 remained an independent prognostic variable for FFS. The level of circulating anti-MUC1-IgG or anti-MUC1-IgM did not correlate with either FFS or OS. Conclusions: A high level of circulating of sMUC1 is associated with a poor outcome in patients with DLCL. The level of circulating anti-MUC1 antibody was not found predictive of survival in DLCL patients in our study. No significant financial relationships to disclose.

T-helper (Th)1/Th2 imbalance in patients with previously untreated B-cell diffuse large cell lymphoma.

T-helper (Th)1/Th2 imbalance has been observed in a variety of pathological conditions, including malignant diseases. We evaluated the Th1/Th2 balance in peripheral blood Th cells by means of intracellular cytokine analysis in 19 patients with previously untreated B-cell diffuse large cell lymphoma (DLCL) and in 18 patients with B-cell DLCL who had achieved complete remission (CR) after chemotherapy. The mean percentage of Th2 in CD4 cells in patients with DLCL (5.00 +/- 2.20) and that of Th1 in CD4+ cells in patients in CR (32.42 +/- 11.30) were significantly increased in comparison with those in healthy volunteers, respectively (Th1; 23.02 +/- 9.45, Th2; 3.25 +/- 0.90; P<0.01). The mean ratio of Th1/Th2 was significantly lower in patients with DLCL (4.74 +/- 0.52) than in patients in CR (9.31 +/- 1.06; P<0.01) and in healthy volunteers (7.25 +/- 0.65; P<0.01). We conclude that the Th1/Th2 balance was polarized to Th2 in untreated DLCL patients and to Th1 in patients in CR, which suggests that a Th1/Th2 imbalance could play a role in lymphomagenesis and durable remission.

Large cell non-Hodgkin lymphoma of childhood

The authors report a study of pediatric patients with advanced diffuse large cell lymphoma (DLCL) who were treated with 2 consecutive regimens, LSA2-L2 and LSA4, over a 25-year-period at the Memorial Sloan-Kettering Cancer Center. They also describe a comparative analysis of two subgroups retrospectively identified as having CD30 positive (+) anaplastic large cell lymphoma (ALCL) and CD30 negative (-) DLCL. To the authors' knowledge, this study represents the longest follow-up on the largest series of uniformly treated pediatric DLCL patients reported to date. A total of 78 consecutive patients were treated for Stage III/IV DLCL. Immunophenotypic data were obtained retrospectively for 52 patients using a panel of monoclonal antibodies against CD30, CD15, CD45, CD45Ro, CD43, epithelial membrane antigen, CD5, BCL-2, cyclin-D, and p53. A disease free survival rate of 72% in patients with advanced stage DLCL using the LSA2-L2 and LSA4 regimens. Of the 78 treated patients, 56 are alive and without evidence of disease with a median follow-up of 120 months (range, 24-312 months). The recurrence rate was significantly higher in the CD30+ ALCL subgroup (33%) than in the CD30- DLCL group (0.04%). Of 52 patients for whom immunophenotypic data were available, 28 had disease of B-cell lineage, 24 had disease of T-cell/null phenotype, 19 were CD30+ (36. 5%), 18 had disease of T-cell phenotype, and 1 had disease of B-cell lineage. The CD30- DLCL cases mostly were of B-cell lineage, had a small risk of treatment failure, and did not develop a recurrence off therapy. A distinct clinical pattern was identified for the CD30+ ALCL group; although these tumors were of T-cell lineage and had a significantly higher rate of late recurrences (median follow-up of 24 months) they all were salvageable. Based on the findings of the current study, the authors propose that T-cell CD30+ ALCL be addressed in the future according to equal dose intensity regimens in induction therapy, as is done for B-cell lymphomas; prolonged periods of maintenance chemotherapy, as is done for T-cell lymphoblastic lymphomas; and no central nervous system prophylaxis beyond the induction period unless other recognized risk factors are present.

Cell proliferation as a long‐term prognostic factor in diffuse large‐cell lymphomas

The relevance of cell proliferation rate--defined as the 3H-thymidine labeling index (3H-dT LI)--in predicting response to treatment (complete remission, CR), freedom from progression (FFP) and overall survival (OS) was evaluated in 86 patients with diffuse large-cell lymphoma (DLCL). The biologic variable was not associated with most of the established clinical factors, such as gender and age of the patient, performance status, B symptoms, tumor bulk, or extranodal disease, but was directly related to stage. 3H-dT LI significantly predicted short- and long-term clinical outcome. In fact, more patients with slowly proliferating DLCL reached CR and had longer median FFP and OS than patients with rapidly proliferating DLCL. Multiple-regression analysis to evaluate the relative contribution of the different biologic and clinical variables in predicting CR, FFP and OS showed that 3H-dT LI and Ann Arbor stage were the only 2 stable factors, which retained their prognostic significance even in the presence of other conventional factors, and that 3H-dT LI was the most powerful as an indicator of risk of death in DLCL patients.

Prognostic factors in stage I and II diffuse large cell lymphoma patients treated with multiagent chemotherapy alone or combined with radiation therapy

Prognostic factors in stage I and II diffuse large cell lymphoma patients treated with multiagent chemotherapy alone or combined with radiation therapy

Prediction of Outcome in Diffuse Large Cell Lymphoma by the Major Histocompatibility Complex Class II (HLA-DR, DP, DQ) and Class I (HLA-A, B, C) Phenotype

Ninety-nine consecutive diffuse large cell lymphoma (DLCL) patients were studied by immunohistochemistry to determine whether clinical outcome was predicted by major histocompatibility complex (MHC) antigen phenotypic expression. Statistically significantly shorter disease free survival (p = 0.005), but not overall survival (p = 0.47), was observed when patient lymphomas failed to express class I MHC antigens. We also observed significantly reduced survival of class II MHC HLA-DP negative patients (p = 0.038). This extends our previous finding of poor outcome with absent class II MHC HLA-DR in DLCL(1) to other MHC antigens and demonstrates that the phenomenon of defective class II antigen expression comprises 16% of these DLCL patients. Known clinical parameters predictive of prognosis were equally distributed between phenotypic groups. These findings indicate that aberrancy of immune phenotype in DLCL is critical to patient outcome and we speculate that loss of MHC expression may confound host immunosurveillance and tumor containment.

A randomized comparison of methotrexate dose and the addition of bleomycin to chop therapy for diffuse large cell lymphoma and other non-Hodgkin's lymphomas cancer and leukemia group B study 7851

In 1978, Cancer and Leukemia Group B initiated a randomized study to determine the usefulness of the addition of bleomycin and/or high-dose methotrexate to standard therapy for the treatment of certain adult non-Hodgkin's lymphomas. Between 1978 and 1985, 177 patients with diffuse large cell lymphoma (DLCL) and 97 patients with other intermediate-grade non-Hodgkin's lymphoma were randomized to receive therapy with three courses of cyclophosphamide, adriamycin, vincristine, and prednisone (CHOP) every 3 weeks with or without low-dose bleomycin by continuous IV infusion. Responders after three courses were further randomized to 3 weeks of therapy with either high-dose methotrexate (3 gm/m2/week intravenously with leucovorin rescue) or standard-dose methotrexate (30 mg/m2/week orally without rescue). Therapy was concluded with three additional courses of CHOP. Neither the addition of low-dose infusion bleomycin nor the use of high-dose rather than low-dose methotrexate had significant effects on response for patients with DLCL; complete response rates for the four treatment programs ranged from 47% to 51%. Median failure-free survival (FFS) for the entire group of DLCL patients was 12 months; 5-year FFS was 27%. There was no significant effect on FFS from the addition of either low-dose bleomycin to CHOP (5-year FFS: CHOP, 28%; CHOP-B, 26%, P = 0.81), or from the use of different doses of methotrexate (5-year FFS: high-dose, 34%; standard-dose, 33%, P = 0.51). Patients with follicular large cell lymphoma, with or without diffuse areas, had a better FFS (5-year FFS, 47%) than patients with DLCL (5-year FFS, 27%), while the patients with the other histopathologic subtypes of diffuse lymphomas had the poorest FFS (5-year FFS, 16%).

Immunobiologic factors predictive of clinical outcome in diffuse large-cell lymphoma.

The prognostic importance of immunobiologic factors in diffuse large-cell lymphoma (DLCL) is studied in 105 consecutive DLCL patients. Multivariate results using the Cox proportional hazards model clearly indicate that the Ki-67 index (P = .002), a marker of cell proliferation activity, and the presence or absence of human leukocyte antigen-DR (HLA-DR) (P = .007) are strong predictors of survival even in the presence of established clinical factors of stage (P = .015) and symptoms (P = .050). Using these four variables, prognostic groups were formed identifying patient groups with varying degrees of risk. The group of patients with three or four risk factors present at the time of diagnosis had a median survival of 4 months compared with a median survival of 59 months for the group with no risk factors. Similarly, prognostic groups for disease-free survival (DFS) were constructed based on the proportional hazards model that involved B versus T phenotype (P = .035) and HLA-DR (P = .054). Median DFS for the patient group with one or two risk factors present was 11 months compared with 43 months with no risk factors present. This study suggests immunobiologic parameters are important predictors of clinical outcome in DLCL patients and are of value in identifying subgroups of patients who have not responded to currently available therapy. The practical significance of this study is to identify parameters that may suggest specific changes in therapy of patient subgroups.