Andrea Janíková

Positron Emission Tomography–Computed Tomography (PET-CT) After Induction Therapy Is Highly Predictive of Patient Outcome in Follicular Lymphoma: Analysis of PET-CT in a Subset of PRIMA Trial Participants

PURPOSE The utility of [(18)F]fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET-CT) in assessing response at the end of induction therapy is well documented in Hodgkins and diffuse large B-cell lymphomas, but its role in follicular lymphoma (FL) remains undetermined. We investigated the prognostic significance of PET-CT performed after first-line therapy in patients with FL treated in the prospective Primary Rituximab and Maintenance (PRIMA) study. PATIENTS AND METHODS Results of PET-CT scans performed after induction immunochemotherapy were recorded retrospectively. Patients went on to either observation or rituximab maintenance per protocol independent of the PET-CT result. Patient characteristics and outcomes were then evaluated. RESULTS Of 122 PET-CT scans performed at the end of the induction immunochemotherapy, 32 (26%) were reported as positive by the local investigator. Initial demographic or disease characteristics did not differ between PET-CT-positive (PET-positive) and PET-CT-negative (PET-negative) patients. PET status correlated with conventional response criteria (P < .001). Patients remaining PET positive had a significantly (P < .001) inferior progression-free survival at 42 months of 32.9% (95% CI, 17.2% to 49.5%) compared with 70.7% (95% CI, 59.3% to 79.4%) in those who became PET negative. PET status, but not conventional response (complete response or complete response unconfirmed v partial response) according to IWC 1999, was an independent predictive factor for lymphoma progression. The risk of death was also increased in PET-positive patients (hazard ratio 7.0; P = .0011). CONCLUSION [(18)F]FDG PET-CT status at the end of immunochemotherapy induction in patients with FL is strongly predictive of outcome and should be considered a meaningful clinical end point in future studies.

Comparison of Subcutaneous Versus Intravenous Administration of Rituximab As Maintenance Treatment for Follicular Lymphoma: Results From a Two-Stage, Phase IB Study

PURPOSE This two-stage phase IB study investigated the pharmacokinetics and safety of subcutaneous (SC) versus intravenous (IV) administration of rituximab as maintenance therapy in follicular lymphoma. PATIENTS AND METHODS In stage 1 (dose finding), 124 patients who responded to rituximab induction were randomly assigned to SC rituximab (375 mg/m2, 625 mg/m2, or an additional group at 800 mg/m2) or IV rituximab (375 mg/m2). The objective was to determine an SC dose that would yield a rituximab serum trough concentration (Ctrough) in the same range as that of IV rituximab. In stage 2, 154 additional patients were randomly assigned (1:1) to SC rituximab (1,400 mg) or IV rituximab (375 mg/m2) given at 2- or 3-month intervals. The objective was to demonstrate noninferior rituximab Ctrough of SC rituximab relative to IV rituximab 375 mg/m2. RESULTS Stage 1 data predicted that a fixed dose of 1,400 mg SC rituximab would result in a serum Ctrough in the range of that of IV rituximab. Noninferiority (ie, meeting the prespecified 90% CI lower limit of 0.8) was then confirmed in stage 2, with geometric mean Ctrough SC:Ctrough IV ratios for the 2- and 3-month regimens of 1.24 (90% CI, 1.02 to 1.51) and 1.12 (90% CI, 0.86 to 1.45), respectively. Overall safety profiles were similar between formulations (in stage 2, 79% of patients experienced one or more adverse events in each group). Local administration-related reactions (mainly mild to moderate) occurred more frequently after SC administration. CONCLUSION The fixed dose of 1,400 mg SC rituximab predicted by using stage 1 results was confirmed to have noninferior Ctrough levels relative to IV rituximab 375 mg/m2 dosing during maintenance, with a comparable safety profile. Additional investigation will be required to determine whether the SC route of administration for rituximab provides equivalent efficacy compared with that of IV administration.

Value of [18F]Fluorodeoxyglucose Positron Emission Tomography in the Management of Follicular Lymphoma: The End of a Dilemma?

BACKGROUND [18F]Fluorodeoxyglucose (FDG) positron emission tomography (PET) is a powerful tool for the imaging of various lymphomas. Despite its high FDG avidity, there is little data on PET in follicular lymphoma (FL). In this work, we present findings concerning PET at staging and posttreatment evaluation in FL. PATIENTS AND METHODS A total of 181 PET scans were evaluated in 117 patients with FL in a retrospective study. Positron emission tomography-based results were compared with conventional staging in 82 patients. Posttreatment PET evaluation was performed in 99 patients; there were comparable progression-free survivals of PET-positive and PET-negative patients. RESULTS Positron emission tomography showed more involvement than computed tomography (CT) with clinical examination in 41 of 82 patients (50%), less in 11 of 82 (13%); the same extension was found in 27 of 82 patients (33%), and 3 patients revealed discordant foci visible on PET only and lymphadenopathy without PET activity (P < .001). Including the results of trephine biopsy, PET finally upstaged FL in 15 of 82 patients (18%), which was projected in change of treatment strategy. There were 73 of 99 negative posttreatment PET scans; 54 of 73 PET-negative patients (74%) remain in complete remission (median follow-up, 27 months); 19 (26%) of them relapsed with median of 12 months. Fourteen of 20 (70%) PET-positive patients relapsed with a median of 4.5 months regardless of findings on CT and subsequent therapy. The difference in relapse rates between PET-positive and PET-negative patients is statistically significant (P < .001). CONCLUSION Positron emission tomography at staging is able to substantially change treatment strategy in an important proportion of patients with FL. Persisting PET positivity after treatment predicts for a high risk of an early relapse and can identify patients with poor prognosis.

Retrospective analysis of 235 unselected patients with mantle cell lymphoma confirms prognostic relevance of Mantle Cell Lymphoma International Prognostic Index and Ki-67 in the era of rituximab: long-term data from the Czech Lymphoma Project Database

Abstract Although a prognostic model (MIPI, Mantle Cell Lymphoma International Prognostic Index) for patients with mantle cell lymphoma (MCL) has been established, its clinical significance for daily practice in the rituximab era remains controversial. Data of 235 unselected patients with MCL from the Czech Lymphoma Project Database were analyzed. MIPI, simplified MIPI (s-MIPI) and Ki-67 proliferation index were assessed for all patients and for a subgroup of 155 rituximab-treated (RT) patients. MIPI divided all patients into subgroups of low-risk (22%), intermediate-risk (29%) and high-risk (49%), with median overall survival 105.8 vs. 54.1 vs. 24.6 months, respectively (p < 0.001). s-MIPI revealed similar results. The validity of both indexes was confirmed in RT patients. We confirmed the Ki-67 index to be a powerful single prognostic factor for overall survival (64.4 vs. 20.1 months, p < 0.001) for all patients and for the RT subset. Our results confirm the clinical relevance of MIPI, s-MIPI and Ki-67 for risk stratification in MCL also in the rituximab era.

Multifunctional immune-modulatory protein HLA-E identified in classical Hodgkin lymphoma: Possible implications

Although the role of the non-classical human leukocyte antigen E (HLA-E) was originally thought to be limited to the development of a maternal tolerance to a semiallogeneic fetal graft, it is now known that HLA-E exerts multiple immunoregulatory functions. The significance of the presence of HLA-E in neoplastic cells and/or background microenvironment cells in classical Hodgkin lymphoma (cHL) is not well characterized. In our study, we evaluated the presence of HLA-E in both neoplastic and background cells in 40 cases of cHL. We found HLA-E in both neoplastic and background cells. There was a positive statistical correlation between the expression of HLA-E in neoplastic cells and the clinical stage of the disease, which indicates an immune-tolerogenic property of this multiple-purpose molecule. The presence of HLA-E in background cells seems to be prognostically neutral but its significance still needs to be determined. The mechanisms regulating the immunopathology of cHL neoplastic cells with respect to the presence of these molecule deserve further studies.

Radiotherapy with rituximab may be better than radiotherapy alone in first-line treatment of early-stage follicular lymphoma: is it time to change the standard strategy?

Early-stage follicular lymphoma (FL) has traditionally been treated with involved-field radiotherapy (RT). Rituximab (R) is a low-toxic, efficient systemic therapy for FL, but there are no data about its clinical impact in early FL. We retrospectively analyzed 93 patients with stage I–II indolent FL treated with RT (n = 65) or RT + R (n = 14) or R alone (n = 14). Median follow-up was 5.0 years for patients with RT, 2.8 years for the RT + R subgroup and 2.5 years for patients treated with R. The complete response rate was 92%, 100% and 86% (not significant) and the median PFS was 3.3 years, not reached and 4.9 years (p = 0.035) for the RT, RT + R and R arms, with no impact on overall survival. R combined with RT seems to give better results in terms of global FL control, but longer follow-up and prospective comparison are needed to verify these results.

A New Prognostic Score for Elderly Patients with Diffuse Large B-Cell Lymphoma Treated with R-CHOP: The Prognostic Role of Blood Monocyte and Lymphocyte Counts Is Absent

Background Absolute lymphocyte count (ALC) and absolute monocyte count (AMC) have been documented as independent predictors of survival in patients with newly diagnosed Diffuse Large B-cell Lymphoma (DLBCL). Analysis of the prognostic impact of ALC and AMC in the context of International Prognostic Index (IPI) and other significant variables in elderly population treated in the R-CHOP regime has not been carried out yet. Methodology/Principal Findings In this retrospective study, a cohort of 443 newly diagnosed DLBCL patients with age ≥60 was analyzed. All patients were treated with the R-CHOP therapy. An extensive statistical analysis was performed to identify risk factors of 3-year overall survival (OS). In multivariate analysis, only three predictors proved significant: Eastern Cooperative Oncology Group performance status (ECOG), age and bulky disease presence. These predictors were dichotomized (ECOG ≥1, age ≥70, bulk ≥7.5) to create a novel four-level score. This score predicted 3-year OS of 94.0%, 77.4%, 62.7% and 35.4% in the low-, low-intermediate, high-intermediate and high-risk groups, respectively (P<0.001). Further, a three-level score was tested which stratifies the population better (3-year OS: 91.9%, 67.2%, 36.2% in the low, intermediate and high-risk groups, respectively) but is more difficult to interpret. Both the 3- and 4-level scores were compared to standard scoring systems and, in our population, were shown to be superior in terms of patients risk stratification with respect to 3-year OS prediction. The results were successfully validated on an independent cohort of 162 patients of similar group characteristics. Conclusions The prognostic role of baseline ALC, AMC or their ratio (LMR) was not confirmed in the multivariate context in elderly population with DLBCL treated with R-CHOP. The newly proposed age-specific index stratifies the elderly population into risk groups more precisely than the conventional IPI and its existing variants.

Successful treatment of steroid-refractory hepatitic variant of liver graft-vs-host disease with pulse cyclophosphamide

OBJECTIVE Corticosteroid-resistant graft-vs-host disease (GVHD) is difficult to manage and is associated with high morbidity and mortality. No standard treatment exists. We have previously seen good results with pulse cyclophosphamide (Cy) in the treatment of liver GVHD in contrast to gastrointestinal GVHD, and here we report results of pulse Cy protocol in the treatment of steroid-refractory hepatitic variant of liver GVHD, with no association to the gut. MATERIALS AND METHODS Cy was infused at a dose of 1,000 mg/m(2). Twenty-nine cyclophosphamide administrations were given to 21 patients. Median time of GVHD onset and Cy administration after transplantation, or donor lymphocyte infusion, were 58 and 69 days, respectively. RESULTS Eleven patients (52%) achieved complete remission and 6 patients (29%) achieved partial remission. Four patients (19%) did not respond, however, their condition stabilized and, upon additional therapy, three achieved partial remission and one complete remission. Overall survival of all 21 patients is 86%, with median and maximal follow-up of 33 and 81 months, respectively. Toxicity was mild and easily manageable without influencing chimerism or disease status. CONCLUSIONS Pulse Cy seems to be an effective treatment for steroid-refractory hepatitic variant of liver GVHD with a good toxicity profile, which may favor its use instead of drugs with more pronounced immunosuppressive effects.

Role of rituximab in treatment of patients with primary central nervous system lymphoma: a retrospective analysis of the Czech lymphoma study group registry

Abstract We have investigated whether the addition of rituximab to methotrexate, procarbazine, vincristine, radiotherapy and cytarabine was associated with improved outcome of primary central nervous system lymphomas (PCNSL). Of 164 patients, 49 received rituximab. Median age was 63 years, median Karnofsky performance score (KPS) was 60 and median follow-up of living patients was 59.5 months. 1- and 2-year PFS were 49.7 and 37.9%, 1- and 2-year OS were 57.0 and 45.3%. Median progression-free survival (PFS), but not overall survival (OS) was significantly better for patients treated with rituximab (22.9 vs. 10.9 months, p = 0.037). In multivariate analysis, age ≤70 years and KPS ≥90 were predictive for PFS and OS, rituximab was an independent prognostic factor for PFS only. In landmark analyses, rituximab was not found beneficial for long-term survivors and no group particularly benefited from rituximab. In conclusion, addition of rituximab was associated with improved PFS, but not OS in this unselected cohort of PCNSL patients.

Gene expression profiling in follicular lymphoma and its implication for clinical practice

Follicular lymphoma (FL) is characterized by an indolent and relapsing course. Recently, the clinical outcome of FL has been distinguished by immune microenvironment-associated gene signatures. In our study, gene expression profiling (GEP) was performed in 31 non-selected patients with follicular lymphoma (FL), 12 of whom were in relapse and the remaining 19 newly diagnosed. A custom oligonucleotide microarray (Agilent 8 × 15K) was used which contained probes for about 3500 genes, including those that had been previously published as demonstrating significant prognostic value. An unsupervised approach was not able to recognize clinically different FLs. As the previously published prognostically relevant gene signatures could not be properly verified, probably due to microarray platform differences, template matching was therefore used in order to define two gene sets with differential gene expression among our samples. These gene sets shared an overrepresentation of genes with similar biological functions and were termed ‘T-CELL’ and ‘PROLIFERATION’ profiles. The ‘poor profile’ was then defined by a high PROLIFERATION score (upper tertile) and/or low T-CELL score (lower tertile). The ‘poor profile’ cohort contained a significantly higher proportion of relapsed cases (p < 0.05, Fishers exact test). Additionally, a comparison of samples from initial diagnosis and from relapse showed significant differences mainly in the T-CELL profile (p = 0.036; χ2). This supports the hypothesis that the number of T-cells and their expression pattern play a major role in FL development.