Intensive treatment strategies may not provide superior outcomes in mantle cell lymphoma: overall survival exceeding 7 years with standard therapies

Martin, Peter; Chadburn, Amy; Christos, Paul J.; Furman, Richard R.; Ruan, Jia; Joyce, Maureen A.; Fusco, E; Glynn, Patricia; Elstrom, Rebecca; Niesvizky, Rubén; Feldman, Eric J.; Shore, Tsiporah B.; Schuster, Michael W.; Ely, Scott; Knowles, DM; Chen‐Kiang, Selina; Coleman, Morton; Leonard, John P.

doi:10.1093/annonc/mdn045

Cited by 70 publications

(41 citation statements)

References 14 publications

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“…1,6,9,[26][27][28][29] The choice to treat or not to treat a patient with MCL may therefore have changed over time because of the increased awareness that not all MCLs are aggressive. 29 In our population-based cohort the SOX11 Ϫ cases and cases with an indolent clinical disease course were, however, not enriched in the later years of the study but were rather present at similar frequencies in the early and late years of the study. It is often difficult to predict the clinical course for a given patient at the time of diagnosis, and the decision to wait with treatment is often based on the judgment of the treating clinician.…”

Section: Discussionmentioning

confidence: 99%

Prognostic role of SOX11 in a population-based cohort of mantle cell lymphoma

Nygren¹,

Wennerholm

Klimkowska³

et al. 2012

Blood

141

102

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The prognostic role of the transcription factor SOX11 in mantle cell lymphoma (MCL) is controversial. We investigated prognostic markers in a population-based cohort of 186 MCL cases. Seventeen patients (9%) did not require any therapy within the first 2 years after diagnosis and were retrospectively defined as having an indolent disease. As expected, indolent MCL had less frequent B symptoms and extensive nodal involvement and 88% of these cases expressed SOX11.In our cohort 13 cases (7.5%) lacked nuclear SOX11 at diagnosis. SOX11 ؊ MCL had a higher frequency of lymphocytosis, elevated level of lactate dehydrogenase (LDH), and p53 positivity. The overall survival in the whole cohort, excluding 37 patients receiving autologous stem cell transplantation, was 3.1 year and in patients with indolent or nonindolent disease, 5.9 and 2.8 years, respectively (P ‫؍‬ .004). SOX11 ؊ cases had a shorter overall survival, compared with SOX11 ؉ cases, 1.5 and 3.2 years, respectively (P ‫؍‬ .014). In multivariate analysis of overall survival, age > 65 (P ‫؍‬ .001), Eastern Cooperative Oncology Group score > 2 (P ‫؍‬ .022), elevated LDH level (P ‫؍‬ .001), and p53 expression (P ‫؍‬ .001) remained significant, and SOX11 lost significance. We conclude that most indolent MCLs are SOX11 ؉ and that SOX11 cannot be used for predicting an indolent disease course. (Blood. 2012;119(18): 4215-4223)

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Section: Discussionmentioning

confidence: 99%

Prognostic role of SOX11 in a population-based cohort of mantle cell lymphoma

Nygren¹,

Wennerholm

Klimkowska³

et al. 2012

Blood

141

102

View full text Add to dashboard Cite

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“…Although conventional chemotherapy induces high-remission rates in previously untreated patients, relapse within a few years is common, contributing to a rather short median survival of 5-7 years. 8,9 The best predictor of survival is tumor proliferation ( Figure 1C). 5 Intensification of first-line treatment has improved progression-free survival, but no curative regimen has been defined so far.…”

Section: Diagnosis Clinical Course and The Origin Of MCLmentioning

confidence: 99%

Mantle cell lymphoma: biology, pathogenesis, and the molecular basis of treatment in the genomic era

Pérez-Galán

Dreyling

Wiestner

2011

Blood

358

310

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Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma of which at least a subset arises from antigen-experienced B cells. However, what role antigen stimulation plays in its pathogenesis remains ill defined. The genetic hallmark is the chromosomal translocation t(11;14) resulting in aberrant expression of cyclin D1. Secondary genetic events increase the oncogenic potential of cyclin D1 and frequently inactivate DNA damage response pathways. In combination these changes drive cell-cycle progression and give rise to pronounced genetic instability. Several signaling pathways contribute to MCL pathogenesis, including the often constitutively activated PI3K/AKT/ mTOR pathway, which promotes tumor proliferation and survival. WNT, Hedgehog, and NF-B pathways also appear to be important. Although MCL typically responds to frontline chemotherapy, it remains incurable with standard approaches. Proteasome inhibitors (bortezomib), mTOR inhibitors (temsirolimus), and immunomodulatory drugs (lenalidomide) have recently been added to the treatment options in MCL. The molecular basis for the antitumor activity of these agents is an area of intense study that hopefully will lead to further improvements in the near future. Given its unique biology, relative rarity, and the difficulty in achieving long-lasting remissions with conventional approaches, patients with MCL should be encouraged to participate in clinical trials. (Blood. 2011; 117(1):26-38) Diagnosis, clinical course, and the origin of MCLMantle cell lymphoma (MCL), a mature B-cell neoplasm defined as a distinct entity in the early 1990s constitutes ϳ 6% of all non-Hodgkin lymphomas (NHLs). 1-4 MCL is typically disseminated at presentation, with a leukemic component in 20%-30% of patients. Classic and blastoid variants are recognized, the latter associated with inferior clinical outcome ( Figure 1A). The genetic hallmark of MCL is the translocation t(11;14)(q13;q32) leading to aberrant expression of cyclin D1, which is not typically expressed in normal lymphocytes ( Figure 1B). However, cyclin D1-negative cases having typical morphology and gene expression profile have been described and often show overexpression of cyclin D2 or D3. 5 Recently, SOX11 has been described as a diagnostic maker that is equally expressed in D1-positive and D1-negative MCL. 6,7 MCL is one of the most difficult to treat B-cell lymphomas. Although conventional chemotherapy induces high-remission rates in previously untreated patients, relapse within a few years is common, contributing to a rather short median survival of 5-7 years. 8,9 The best predictor of survival is tumor proliferation ( Figure 1C). 5 Intensification of first-line treatment has improved progression-free survival, but no curative regimen has been defined so far. 2,3 In MCL, as in chronic lymphocytic leukemia (CLL), the variable region of the expressed immunoglobulin heavy chain gene (IGHV) displays either germline configuration (Ig-unmutated), as found in naive B cells, or contains somatic mutations (Ig-mutated), indicat...

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“…To determine whether anti-third-party CTLs are endowed with antilymphoma cell reactivity, we initially tested their ability to kill the BL-44 and Granta519 cell lines, both of which represent highly aggressive malignancies (22,23). As can be seen in Fig.…”

Section: Allogeneic and Autologous Anti-third-party Ctls Induce Apoptmentioning

confidence: 99%

TCR-Independent Killing of B Cell Malignancies by Anti–Third-Party CTLs: The Critical Role of MHC–CD8 Engagement

Lask

Goichberg

Cohen

et al. 2011

The Journal of Immunology

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We previously demonstrated that anti–third-party CTLs (stimulated under IL-2 deprivation against cells with an MHC class I [MHC-I] background different from that of the host and the donor) are depleted of graft-versus-host reactivity and can eradicate B cell chronic lymphocytic leukemia cells in vitro or in an HU/SCID mouse model. We demonstrated in the current study that human allogeneic or autologous anti–third-party CTLs can also efficiently eradicate primary non-Hodgkin B cell lymphoma by inducing slow apoptosis of the pathological cells. Using MHC-I mutant cell line as target cells, which are unrecognizable by the CTL TCR, we demonstrated directly that this killing is TCR independent. Strikingly, this unique TCR-independent killing is induced through lymphoma MHC-I engagement. We further showed that this killing mechanism begins with durable conjugate formation between the CTLs and the tumor cells, through rapid binding of tumor ICAM-1 to the CTL LFA-1 molecule. This conjugation is followed by a slower second step of MHC-I–dependent apoptosis, requiring the binding of the MHC-I α2/3 C region on tumor cells to the CTL CD8 molecule for killing to ensue. By comparing CTL-mediated killing of Daudi lymphoma cells (lacking surface MHC-I expression) to Daudi cells with reconstituted surface MHC-I, we demonstrated directly for the first time to our knowledge, in vitro and in vivo, a novel role for MHC-I in the induction of lymphoma cell apoptosis by CTLs. Additionally, by using different knockout and transgenic strains, we further showed that mouse anti–third-party CTLs also kill lymphoma cells using similar unique TCR-independence mechanism as human CTLs, while sparing normal naive B cells.

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Intensive treatment strategies may not provide superior outcomes in mantle cell lymphoma: overall survival exceeding 7 years with standard therapies

Abstract: Outcomes with standard approaches can yield similar survival to that achieved with more intensive approaches. Biases may account for the perceived superiority of aggressive strategies.

Cited by 70 publications

References 14 publications

Prognostic role of SOX11 in a population-based cohort of mantle cell lymphoma

Prognostic role of SOX11 in a population-based cohort of mantle cell lymphoma

Mantle cell lymphoma: biology, pathogenesis, and the molecular basis of treatment in the genomic era

TCR-Independent Killing of B Cell Malignancies by Anti–Third-Party CTLs: The Critical Role of MHC–CD8 Engagement

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