David Šálek

Central nervous system involvement in mantle cell lymphoma: clinical features, prognostic factors and outcomes from the European Mantle Cell Lymphoma Network

BACKGROUND Central nervous system (CNS) involvement in mantle cell lymphoma (MCL) is uncommon, and the manifestations and natural history are not well described. PATIENTS AND METHODS We present the data on 57 patients with MCL who developed CNS involvement, from a database of 1396 consecutively treated patients at 14 institutions. RESULTS The crude incidence of CNS involvement was 4.1%, with 0.9% having CNS involvement at diagnosis. Blastoid histology, B-symptoms, elevated lactate dehydrogenase, Eastern Cooperative Group performance status ≥2 and a high Mantle Cell Lymphoma International Prognostic Index score were enriched in the cohort with CNS involvement, and the presence of ≥1 of these features defined a high-risk subset (an actuarial risk of CNS involvement 15% at 5 years) in a single-institution subset. The median time to CNS relapse was 15.2 months, and the median survival from time of CNS diagnosis was 3.7 months. The white blood cell count at diagnosis <10.9 × 10⁹/l, treatment of CNS involvement with high-dose anti-metabolites, consolidation with stem cell transplant and achievement of complete response were all associated with improved survival. CONCLUSIONS In MCL, CNS involvement is uncommon, although some features may predict risk. Once manifest outlook is poor; however, some patients who receive intensive therapy survive longer than 12 months.

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.

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.

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.

Frontline intensive chemotherapy improves outcome in young, high-risk patients with follicular lymphoma: pair-matched analysis from the Czech Lymphoma Study Group Database

Abstract Optimal frontline treatment in younger high tumor-burden risk follicular lymphoma patients remains a challenge given the reduced efficacy of standard immunochemotherapy (R-CHOP) in widespread disease and unclear role of intensive induction. The retrospective non-randomized pair-matched (1:3) analysis compared 48 intermediate/high Follicular Lymphoma International Prognostic Index (FLIPI) patients receiving intensive rituximab sequential chemotherapy (R-SQ) with 144 random controls (R-CHOP) matched for age, FLIPI score, and maintenance delivery. Complete response rates were 91.7% and 74.1%, respectively (p = .038). After a median follow-up of 8.8 (R-SQ) and 6.5 years (R-CHOP), 5-year time to treatment failure, progression-free survival, and overall survival were 80.9%, 83.2%, and 100% and 57.5%, 60.3%, and 92.1% (p = .0044; p = .0047; p = .22), respectively. Intensive treatment was accompanied by higher acute hematologic toxicity and infections, comparable non-hematologic toxicity, and incidence of secondary malignancies. Intensive induction demonstrates superior long-term disease control compared to R-CHOP, with higher acute hematologic toxicity, but without acute treatment-related mortality. Further studies are needed to define ultra-high-risk FL patients benefiting most from treatment intensity.

Detection of minimal residual disease in mantle cell lymphoma—establishment of novel eight-color flow cytometry approach

Minimal residual disease (MRD) detection is an essential tool for therapy response assessment in a considerable number of hematooncologic disorders, including mantle cell lymphoma (MCL). Flow cytometry (FCM) ranks among the most effective approaches, which allows rapid sample processing and compete successfully with highly sensitive molecular methods like polymerase chain reaction. Because FCM is ordinarily applied to detect MRD in B‐lineage diseases like chronic lymphocytic leukemia, a similar method could be used in MCL. We decided to test our novel eight‐color FCM approach in MCL MRD detection.

Complex analysis of the TP53 tumor suppressor in mantle cell and diffuse large B-cell lymphomas

Mutations and deletions of the tumor suppressor TP53 gene are the most frequent genetic alterations detected in human tumors, though they are rather less frequent in lymphomas. However, acquisition of the TP53 mutation was demonstrated to be one of the characteristic markers in mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL) and prognostic value of the TP53 status has been recognized for these diseases. We present the complex analysis of the TP53 aberrations in 57 cases of MCL and 131 cases of DLBCL. The TP53 status was determined by functional analyses in yeast (FASAY) followed by cDNA and gDNA sequencing. The level of the p53 protein was assessed by immunoblotting and loss of the TP53-specific locus 17p13.3 was detected by FISH. Altogether, we detected 13 TP53 mutations among MCL cases (22.8%) and 29 TP53 mutations in 26 from 131 DLBCL cases (19.8%). The ratio of missense TP53 mutations was 76.9% in MCL and 82.8% in DLBCL. The frequency of TP53 locus deletion was rather low in both diseases, reaching 9.3% in MCL and 15.3% in DLBCL. The presence of TP53 mutation was associated with shorter overall survival (OS) and progression-free survival (PFS) in MCL. Among DLBCL cases, the TP53 mutations shortened both OS and PFS of patients treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) and decreased both OS and PFS of patients with secondary DLBCL disease.

Alternating R‐CHOP and R‐cytarabine is a safe and effective regimen for transplant‐ineligible patients with a newly diagnosed mantle cell lymphoma

Implementation of cytarabine into induction therapy became standard of care for younger patients with mantle cell lymphoma (MCL). On the basis of its beneficial impact, many centers incorporated cytarabine at lower doses also into first‐line treatments of elderly patients. We conducted a multicenter observational study that prospectively analyzed safety and efficacy of alternating 3 + 3 cycles of R‐CHOP and R‐cytarabine for newly diagnosed transplant‐ineligible MCL patients. A total of 73 patients were enrolled with median age 70 years. Most patients had intermediate (39.7%) and high‐risk (50.7%) disease according to MCL international prognostic index. Rituximab maintenance was initiated in 58 patients. Overall response rate reached 89% by positron emission tomography–computed tomography, including 75.3% complete remissions. Two patients (2.7%) did not complete the induction therapy because of toxicity. Three patients (4.1%) were considered nonresponders, which led to therapy change before completion of induction. Estimated progression‐free survival and overall survival were 51.3% and 68.6% at 4 years, respectively. Mantle cell lymphoma international prognostic index, bulky disease (≥ 5 cm), and achievement of positron emission tomography–negativity independently correlated with progression‐free survival. Grade 3 to 4 hematologic and nonhematologic toxicity was documented in 48% and 20.5% patients, respectively. Alternation of R‐CHOP and R‐cytarabine represents feasible and very effective regimen for elderly/comorbid MCL patients. This study was registered at GovTrial (clinicaltrials.gov) NCT03054883.

Microvessel density of mantle cell lymphoma. A retrospective study of its prognostic role and the correlation with the Ki-67 and the mantle cell lymphoma international prognostic index in 177 cases.

The clinical course and therapy of mantle cell lymphoma (MCL) are heterogeneous and often unsatisfactory. Prognostic factors are needed to stratify the patients. Microvessel density (MVD) has prognostic significance in some malignancies. There is little information about the vasculature of MCL, although some antiangiogenic drugs are in use. We studied MVD using systematic uniform random sampling and unbiased counting frames in immunohistochemical reactions with anti-CD34 antibody in pre-therapeutic extramedullary MCL samples of 177 patients. We analyzed the relationship of MVD to overall survival (OS) and progression-free survival (PFS), as well as to proliferative activity (Ki-67), mantle cell lymphoma prognostic index (MIPI), morphological variant, pattern of growth, and localization. MVD varied widely: range 54.6–503.6 vessels/mm2, median 158.2 vessels/mm2. Higher MVD was associated with bone marrow infiltration at the time of diagnosis (P = 0.001). High MVD was associated with significantly worse OS (P = 0.04) only in patients treated with non-intensive (conventional) therapy. MVD correlated positively with MIPI scores but not with the proliferation, morphological variant, growth pattern, or localization. Univariate analysis identified a prognostic influence of morphological variant, MIPI, and proliferative activity on OS and PFS and a prognostic influence of bone marrow infiltration at the time of diagnosis on PFS. Multivariate analysis showed prognostic influence of MIPI and proliferative activity on OS and PFS only. In conclusion, this is the first clinicopathological study of MVD of MCL with long-term follow-up showing negative prognostic trends of high MVD in MCL and positive correlation of MVD and MIPI.

Transmission of t(11;14)-positive cells by allogeneic stem cell transplant: 10-year journey to mantle cell lymphoma

Mantle cell lymphoma (MCL) is considered, with some exceptions, to be one of the most aggressive lymphomas, with relatively short median survival [1]. Th e biological hallmark of MCL is t(11;14)(q13;q32) resulting in cyclin D1 overexpression, which is not usually expressed in normal B cells [2]. Although the initial oncogenic translocation is acquired at the pre-B stage during the V(D)J recombination in the bone marrow [3], MCL is composed of mature B cells that grow in the mantle zone of lymphatic follicles and express the corresponding phenotype. To date, the oncogenic steps from the early event to the development of MCL have not been well documented. Rare cases of donor-derived malignancies can provide better insights into the biology and growth of different tumors under real conditions.