T-Cell Frequencies In MCL Are Of Prognostic Importance In a Large Population-Based Cohort

Abstract Mantle cell lymphoma is a non-Hodgkin lymphoma with, in general, a poor prognosis. A minor subset of patients with an indolent disease course has however been recognized (1,2). The various growth patterns of MCL, i.e. mantle zone (MZ), nodular (N) or diffuse (D) is assumed to correlate to stage and to disease course. The genetic aberrations underlying the pathogenesis are well defined and correlate to high tumour cell proliferation and poor prognosis. However, the effect of the lymphoma microenvironment in disease development and sustainability is largely unknown. We have used flow cytometry to investigate the non-malignant cell composition of the lymph node microenvironment in a population-based cohort of 154 MCL cases diagnosed from January 1, 1998 to December 31, 2012. Flow cytometry analyses of lymph nodes, performed as part of the diagnostic process, were used to evaluate percentages of tumour cells, remaining non-malignant B-cells and T-cell subsets (CD3+, CD3+CD4+, CD3+CD8+). As lymph node T-cell numbers reflect a high tumor load in the lymph node we also investigated the CD4/CD8 ratio, which is not dependent on T-cell percentage. Data from 26 non-malignant lymph nodes were used for comparison. T-cell percentages are shown in Table 1. Clinical and other pathological parameters of the MCL cases, including MIPI, cell morphology, tumor growth pattern and cell proliferation were also evaluated. Indolent disease (n=15), defined here as requirement of treatment > two years from diagnosis, was associated with higher amount of CD3, CD3+CD4+ and higher CD4/CD8 ratio (p=0.0429, p=0.0211 and p= 0.0032 respectively). Higher tumor cell proliferation correlated negatively with the CD4/CD8 ratio (p= 0.0007). There was a significant difference in CD3 percentages between reactive lymph nodes and MCL irrespective of growth pattern (all p<0.001). Within the entity of MCL, CD3 percentage were higher in MZ growth pattern compared to N and D (p=0.014 and p<0.001, respectively). CD3 percentages were also higher in N compared to D growth pattern (p=0.0086). CD4/CD8 ratio decreased according to growth pattern (MZ compared to N p=0.048, MZ compared to D p=0.003). Blastoid and classical MCL variants did not differ significantly in amount of CD3, CD3+CD4+, CD3+CD8+, CD19 or CD4/CD8 ratio (all p>0.05). Furthermore, male sex negatively correlated with CD4/CD8 ratio (p=0.0268). Age was not associated to T-cell percentages, CD4/CD8 ratio or growth pattern. In survival analysis a high CD4/CD8 ratio was positively correlated with OS (p= 0.0175).Table 1T-cell percentages (% of mononuclear cells) and CD4/CD8 ratio in reactive lymph nodes and MCL with different growth patterns (marginal zone (MZ), nodular (N) and diffuse (D)) (median, range).CD3CD4CD8CD4/CD8Reactive lymph nodes n=2652.9 (17.6-75.6)39.6 (14.1-63.4)10.0 (2.4-19.2)4.2 (2.1-6.9)MCL MZ n=2530.4 (10.9-84.0)17.4 (7.4-63.2)7.9 (1.2-21.1)3.1 (0.9-7.7)MCL N n=2716.7 (2.3-71.4)9.6 (1.1-58.9)5.4 (1.1-15.2)1.8 (0.6-8.6)MCL D n=469.9 (2.0-43.7)5.5 (0.7-37.0)4 (0.4-18.1)1.6 (0.4-10.4) In conclusion, our data show that the normal lymph node microenvironment is better preserved in indolent MCL and MCL with mantle zone growth pattern. The CD4/CD8 ratio is independent of lymph node tumor burden and high CD4/CD8 ratio was found to correlate with better OS. MCL tumor cells have recently been reported to impair T-cell responses (3). Our results could reflect a disease evolution towards lower tumor cell dependency on signals from the microenvironment and/or as a lymphoma mediated suppression of immune mechanisms for tumor control in aggressive MCL. References: 1. Martin, P. et al. Outcome of deferred initial therapy in mantle-cell lymphoma. J. Clin. Oncol., 2009, 27(8): p. 1209–13 2. Nygren, L. et al. Prognostic role of SOX11 in a population-based cohort of mantle cell lymphoma. Blood, 2012. 119(18): p- 4125–23. 3. Wang, L. et al. Immune evasion evasion of mantle cell lymphoma: expression of B7-H1 leads to inhibited T-cell response to and killing of tumor cells. Haematologica, 2013. Disclosures: No relevant conflicts of interest to declare.

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Cell Proliferation (Ki-67) As Prognostic Marker in Mantle Cell Lymphoma.

Blood ◽

10.1182/blood.v120.21.2677.2677 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2677-2677 ◽

Cited By ~ 3

Author(s):

Eva Hoster ◽

Wolfram Klapper ◽

Andreas Rosenwald ◽

Heinz-Wolfram Bernd ◽

Sylvia Hartmann ◽

...

Keyword(s):

Cell Proliferation ◽

Prognostic Factors ◽

Lymph Node ◽

Mantle Cell Lymphoma ◽

Prognostic Marker ◽

Cell Lymphoma ◽

High Dose ◽

Ki 67 ◽

Prognostic Relevance ◽

Mantle Cell

Abstract Abstract 2677 Introduction: The percentage of proliferating cells evaluated on diagnostic tumor samples has been shown to be of high prognostic relevance in Mantle Cell Lymphoma (MCL) patients. As MCL is relatively rare, evaluation of proliferation has so far mostly been based on smaller patient cohorts that were retrospectively collected and inhomogenously treated. In 2004, the European MCL Network initiated two large European randomized trials for younger (“MCL Younger” trial) and older (“MCL Elderly” trial) MCL patients, primary results of which have recently been reported (Kluin-Nelemans et al., NEJM 2012, Hermine et al., ASH 2010). We aimed to clarify the prognostic relevance of the proliferation marker Ki-67 using pooled data from these two trials. Patients and Methods: Patients with histologically confirmed and previously untreated MCL of stages II-IV up to 65 years of age were randomly assigned in “MCL Younger” to either 6 cycles R-CHOP followed by myeloablative radio-chemotherapy and autologous stem cell transplantation (ASCT), or 6 cycles alternating R-CHOP/R-DHAP followed by high-dose-Ara-C containing conditioning and ASCT. Patients aged 60 years or older and not eligible for high-dose therapy were randomly assigned in “MCL Elderly” to either 8 cycles of R-CHOP or 6 cycles of R-FC; responding patients were subsequently randomized to either interferon-alpha or rituximab maintenance until progression. Histological diagnosis was confirmed by central review within the European MCL Pathology Panel. The percentage of Ki-67 positive cells was counted on diagnostic lymphoma samples among 2 times 100 cells by the central pathology labs according to published consensus guidelines (Klapper et al., J Hematopathology 2009). The outcome measures were time to treatment failure (TTF) from treatment initiation to stable disease, progression, or death from any cause, and overall survival (OS) from trial registration to death from any cause. We investigated the prognostic value of proliferation as a quantitative marker with regards to TTF and OS in univariable Cox regression and evaluated the previously established cut-off values of 10% and 30% (Determann et al., Blood 2008) using Kaplan-Meier estimates and log rank tests. We also adjusted for clinical prognostic factors (MIPI, Hoster et al., Blood 2008). Results: Counted Ki-67 values were available in 51% (543) of 1057 randomized patients (material not available, 30%; Ki-67 evaluation not possible due to technical reasons, 16%). The origin of tumor tissue was lymph node in 81%, gastrointestinal tract in 12%, bone marrow in 4% and other in 3%. The median proliferation rate was 20% (range, 0–97%; interquartile range, 12–34%) and did not significantly differ between tissue origins. In univariable analysis, a 10% higher proliferation rate was associated with hazard ratios of 1.18 (95% confidence interval, 1.12 to 1.25, p<0.0001) for TTF and 1.23 (95% CI, 1.15 to 1.31, p<0.0001) for OS. Patients with Ki-67 ≥ 30% had median TTF and OS of 19 and 45 months compared to 64 months and not reached with Ki-67 < 30% (p<0.0001 each). Patients with Ki-67 < 30% and either ≥ 10% or < 10% had similar TTF and OS. The separation of a high risk group as defined by Ki-67 ≥ 30% was consistently seen within “MCL Younger” and “MCL Elderly” as well as within the 4 different induction treatment arms. The prognostic impact of proliferation was independent of the MIPI prognostic score (adjusted hazard ratio for TTF, 1.11, 95% CI, 1.05 – 1.17, p=0.0005; for OS, 1.14, 1.07–1.23, p=0.0001), which was also independently highly prognostic (p<0.0001). Almost identical results were seen when the analyses were restricted to lymph node samples. Conclusions: Cell proliferation was confirmed as important biological prognostic marker independent of clinical prognostic factors on a large cohort of MCL patients uniformly treated within clinical trials. Since the evaluation of Ki-67 has been standardized, guidelines (e.g. Dreyling et al., Ann Onc, in press) recommend applying this parameter in clinical routine. Further analyses will focus on the joint correlation of Ki-67, MIPI and minimal residual disease with outcome to potentially allow a more individualized therapeutic approach in MCL patients. On behalf of the European Mantle Cell Lymphoma Network. Disclosures: No relevant conflicts of interest to declare.

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Blastoid Variant Mantle Cell Lymphoma Expressing Aberrant CD3 and CD10 with Concurrent Small Lymphocytic Lymphoma: Establishment of a Clonal Relationship by B- and T-Cell Receptor Gene Rearrangements

Case Reports in Hematology ◽

10.1155/2018/8303571 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10

Author(s):

Christopher L. Felten ◽

Joel A. Chan ◽

Dulce R. DeCastro ◽

Jean Lopategui ◽

Swapnil P. Rajurkar

Keyword(s):

Lymph Node ◽

T Cell ◽

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

Receptor Gene ◽

B Cell Lymphoma ◽

Cell Receptor ◽

Small Lymphocytic Lymphoma ◽

Diagnostic Challenge ◽

Mantle Cell

Mantle cell lymphoma (MCL) is an aggressive non-Hodgkin B-cell lymphoma typically expressing CD19, CD20, CD5, FMC-7, CyclinD1, and SOX-11 and harboring the IgH/CCND1 translocation. We report a blastoid variant of mantle cell lymphoma (MCL) involving an inguinal lymph node that, in addition to classical phenotypic and genetic findings, also aberrantly coexpresses surface CD10 and cytoplasmic CD3. Small lymphocytic lymphoma (SLL) was also present in the same lymph node and in the bone marrow. B- and T-cell gene rearrangement studies by PCR show the MCL and SLL to be clonally related. Expression of multiple aberrant antigens and concurrent lymphomas of different classifications can cause a diagnostic challenge. Awareness of such a presentation and integration of the data from morphologic evaluation, flow cytometry, immunohistochemistry, and FISH studies is required for proper diagnosis, prognosis, and therapy.

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Tumor Cell Proliferation (Ki-67 Index) Overcomes Cytology and Growth Pattern As Prognostic Factor in Mantle-Cell Lymphoma – Results from Randomized Trials of the European MCL Network

Blood ◽

10.1182/blood.v124.21.2977.2977 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2977-2977 ◽

Cited By ~ 4

Author(s):

Eva Hoster ◽

Andreas Rosenwald ◽

Francoise Berger ◽

Heinz-Wolfram Bernd ◽

Sylvia Hartmann ◽

...

Keyword(s):

Cell Proliferation ◽

Tumor Cell ◽

Mantle Cell Lymphoma ◽

Growth Pattern ◽

Randomized Trials ◽

Cell Lymphoma ◽

Tumor Cell Proliferation ◽

Ki 67 ◽

Mantle Cell ◽

Diffuse Growth

Abstract On Behalf of the European MCL Pathology Panel Introduction: Mantle-cell lymphoma (MCL) is an aggressive B-cell lymphoma with a median overall survival (OS) of 5 years, but clinical course varies considerably. This variability has been partly explained by clinical characteristics forming the MIPI (Hoster et al., JCO 2014), but also biological and histological features such as tumor cell proliferation (Ki-67 index), cytology, or growth pattern (Tiemann et al., BJH 2005). Immuno-chemotherapy induction represents the current standard of care, in younger patients including high-dose cytarabine and followed by autologous stem cell transplantation, whereas older patients benefit from rituximab maintenance (Dreyling et al., Ann Oncol 2013). In 2004, the European MCL Network started two large randomized trials, MCL Younger and MCL Elderly, for previously untreated MCL patients. Histopathological features of diagnostic samples were centrally assessed by the European MCL Pathology Panel. Since MCL is relatively rare, evaluations of prognostic factors were mostly based on smaller, retrospectively collected patient cohorts. We now aimed to comparatively evaluate the prognostic value of Ki-67 index, cytology, and growth pattern using the data of these trials. Methods: The Ki-67 index was counted according to published guidelines (Klapper et al., J Hematopathol 2009). MCL cytology was classified as classic, small-cell (B-CLL-like), pleomorphic (DLBCL-like), or blastic (LB-like) (Vogt and Klapper, Histopathology 2013). MCLs with pleomorphic or blastic cytology were combined to blastoid MCL. The growth pattern was classified as diffuse (≤50% nodular) or non-diffuse (>50% nodular or predominantly mantle-zone pattern). The prognostic relevance of these markers was evaluated with respect to OS, adjusting for MIPI score. Results: Of 1012 trial patients with MCL, Ki-67 index, cytology, or growth pattern were available in 50%, 61%, and 47%, respectively. Reasons for missing information were mainly insufficient material or staining. Median Ki-67 index was 20% (2%-97%). 88% had classic MCL, 2% small-cell, 7% pleomorphic and 3% blastic cytology, summing up to 10% with blastoid MCL. 63% of patients had a diffuse growth pattern. Higher Ki-67 index, blastoid MCL, and diffuse growth were each associated with higher MIPI score. Growth pattern was not clearly associated with Ki-67 index or cytology, whereas pleomorphic (median Ki-67 index 39%, range 7%-90%) or blastic MCL (median 80%, 29%-97%) displayed a substantially higher Ki-67 index compared non-blastoid MCL (median 19%, 2%-95%). In univariable analyses, the adjusted OS hazard ratios for higher Ki-67 index (10% increase), blastoid MCL, or diffuse growth were 1.16 (95% CI 1.09-1.24, p<0.0001), 1.91 (1.34-2.72, p=0.0004), and 1.16 (0.84-1.60, p=0.38), respectively. In multivariable analyses, Ki-67 index was more relevant (adjusted hazard ratio 1.12, 1.04-1.22, p=0.0032) than blastoid MCL (1.46, 0.94-2.29, p=0.095), whereas growth pattern was not prognostic. Accordingly, patients with Ki-67 index ≥30% had substantially inferior OS than patients with Ki-67 index <30% in both, blastoid and non-blastoid MCL (Figure 1). Conclusions: In a large cohort of MCL patients treated in randomized trials according to current guidelines, tumor cell proliferation (Ki-67 index) was a powerful prognostic marker, superior to cytology and growth pattern, and independent of clinical prognostic factors. The Ki-67 index further stratified patients with non-blastoid as well as patients with blastoid MCL into groups with substantially different survival. Thus, standardized assessment of the Ki-67 index (Klapper et al. J Hematopathol 2009) should be routinely performed in clinical practice to allow a more comprehensive individual risk estimation of MCL patients. Further analyses will aim at the biological basis of this prognostic effect. Figure 1: Overall survival according to Ki-67 index (< vs. ≥ 30% from Determann et al., Blood 2008) in patients with non-blastoid (left) or blastoid (right) mantle-cell lymphoma (MCL) Figure 1:. Overall survival according to Ki-67 index (< vs. ≥ 30% from Determann et al., Blood 2008) in patients with non-blastoid (left) or blastoid (right) mantle-cell lymphoma (MCL) Figure 2 Figure 2. Disclosures Dreyling: Roche: Honoraria, Research Funding. Klapper:Roche: Research Funding.

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