Blastoid Variant Research Articles

Final Results of a Phase 1-2 Study of Vorinostat (SAHA), Cladribine, and Rituximab (SCR) Relapsed B-Cell Non-Hodgkin’s Lymphoma and Previously Untreated Mantle Cell Lymphoma

Abstract Background: Mantle cell lymphoma (MCL) is incurable with chemo-immunotherapy. Epigenetic modifications including altered DNA methylation and histone acetylation previously identified in MCL has provided the rationale for using the combination of a hypomethylating agent and a histone deactylase inhibitor. We aimed to study a combination of agents with differing mechanisms of action including vorinostat (SAHA), cladribine, and rituximab (SCR) in lymphoid malignancies. Methods: In this single arm, open label, investigator initiated Phase 1-2 study performed at two centers, we enrolled 65 patients with non-Hodgkin’s lymphomas (NHL) including diffuse large B-cell lymphoma, chronic lymphocytic leukemia (CLL), indolent NHL, and mantle cell lymphoma (MCL). All patients were treated with cladribine 5 mg/m2 IV (days 1-5), rituximab 375 mg/m2 IV (weekly x 4 for cycle 1 and 1x/month) and vorinostat orally once daily (days 1-14) every 28 days for up to 6 cycles. All responding patients were eligible for Rituximab maintenance every 2-3 months as part of standard of care treatment per investigator discretion. The phase 1 portion of the study enrolled patients with relapsed disease in a standard 3+3 dose escalation design using 3 dose levels of vorinostat 200 mg, 300 mg, 400 mg). The primary endpoint of the phase 1 study was dose limiting toxicity (DLT). Phase 2 (n = 55) included relapsed patients (n= 17) with MCL, CLL, FL, and previously untreated MCL (n=38). Primary objectives for phase 2 were objective response rate (ORR), tolerability, and toxicity. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). The analysis was done by intent to treat. Scientific correlative studies included analysis of CD20 expression, histone acetylation, gene microarray, qRT-PCR and HELP methylation analysis. This study is registered with clinicaltrials.gov (NCT00764517). Findings: The median age for phase 1 and 2 was 64 (range 45-84). No DLTs were seen in the Phase 1 and the achieved phase 2 starting dose was vorinostat 400 mg po (days 1-14) combined with cladribine 5mg/m2 IV (days 1-5), and rituximab 375 mg/m2 (weekly x 4 for cycle 1 and 1x/month for cycles 2-6). For Phase 2, the ORR (CR + PR) for relapsed patients was 47% (8/17). For the previously untreated MCL cohort (n=38), 33 (87%) of subjects were male, 36 (95%) had stage 4 disease, and 7 (19%) had blastoid histology. 11 (29%) had a high MIPI. ITT ORR in this cohort was 97% (37/38) with 31/37 (84%) attaining a CR-one patient was not evaluable due to an infusion reaction necessitating removal from the study during cycle 1. CR was achieved in 31/34 (91%) of patients without blastic MCL.The median PFS and OS for the relapsed cohort were 25 months and 25.7 months respectively. For the previously untreated cohort, at a median follow up of 18.7 months (.36-41 months), 7 patients had relapsed and 4 had died. 3 of the 7 relapses occurred in patients with blastoid MCL. Of the 4 deaths, 1 patient died due to a cardiac event while in CR. The median PFS (Figure 1A) and OS (Figure 1B) for this previously untreated cohort could not be estimated because the curves did not reach the .5 level. PFS and OS will be updated at the meeting. Primary ≥ 3 toxicities (%) for phase 1 and 2, irrespective of drug attribution/causality, were hematologic. Despite the high frequency of neutropenia, ≥ grade 3 neutropenic fever or infections were relatively low (<10%). Fatigue was the most frequent ≥ 3 non-hematologic toxicity. There was one death due to pulmonary hemorrhage in a patient with relapsed MCL with significant pulmonary involvement. Correlative studies showed that treatment with this regimen resulted in dramatic changes in mRNA expression of multiple tumor suppressor genes including DUSP1, DUSP 2, and p53, as well as changes in CD20 mRNA levels, but increases were not uniform and did not correlate with response or outcome. Conversely, differences in cyclin D1 genotype known to encode a splice variant that is associated with increased risk of multiple cancers as well as nuclear localization of the protein, was associated with blastic histology and found to be inversely related to response. Conclusions: The SCR regimen is an active and well tolerated regimen, especially in patients with previously untreated MCL. Similar to other current MCL induction regimens, patients with MCL blastoid variant appear to have inferior outcomes. Figure 1A Figure 1A. Figure 1B Figure 1B. Disclosures Spurgeon: Merck Pharmaceuticals: Research Funding. Off Label Use: vorinostat off label for the treatment of CLL and NHL.

Primary gastrointestinal mantle cell lymphoma: a retrospective study.

Primary gastrointestinal tract mantle cell lymphoma is very rare. There is paucity of literature regarding natural history and outcome of this unusual entity. The aim of the present study was to analyze clinical profile, epidemiological parameters, and outcome of primary gastrointestinal mantle cell lymphoma patients treated at our institute. This was a retrospective observational study of consecutive patients diagnosed with primary gastrointestinal mantle cell lymphoma at our institute between 2001 and 2012. A total of seven patients, all males with a median age of 67.7years, were diagnosed with primary gastrointestinal mantle cell lymphoma. Sites involved were the stomach, colon, and rectum. Blastoid and diffuse variants were observed in three patients each, and one patient had nodular pattern. Five patients received cyclophosphamide, adriamycin, vincristine, and prednisolone (CHOP) chemotherapy. Only one patient achieved complete remission and remained disease free for 21months before being lost to follow up. The remaining four patients had inadequate response to CHOP chemotherapy with a median survival of 6months. Cyclophosphamide, vincristine, prednisolone (CVP) was given to one patient in view of poor performance status. He had progressive disease and died after first cycle of chemotherapy. One patient is currently undergoing treatment and receiving rituximab with chemotherapy. Primary gastrointestinal mantle cell lymphoma is highly aggressive with the Mantle Cell Lymphoma International Prognostic Index (MIPI) scores in high-risk group; survival is poor compared to nodal mantle cell lymphoma involving the gastrointestinal tract; patients respond poorly to CHOP chemotherapy. As majority of patients are elderly and not eligible for transplant, the use of rituximab in remission induction and maintenance should be considered to improve outcome of these patients.

Blastoid Variant Mantle Cell Lymphoma with Complex Karyotype Including 11q Duplication

We describe a case of blastoid mantle cell lymphoma with a complex karyotype. The blastoid variant is a rare type of non-Hodgkin lymphoma exhibiting an aggressive clinical course. Mantle cell lymphoma is a distinct entity of mature B-cell neoplasms genetically characterized by the presence of t(11;14). In the present case, conventional analysis revealed structural abnormalities of chromosomes 2, 4, 6, 10, 13, and 19, along with 3 additional marker chromosomes. The derivative 1 chromosome determined in the case was a result of t(1p;11q). Our interesting finding was the presence of a different translocation between 11q and chromosome 1 in addition to t(11;14). Thus, the resulting 11q duplication was believed to additionally increase the enhanced expression of cyclin D1 gene, which is responsible in the pathogenesis of the disease. Fluorescence in situ hybridization method by the t(11;14) probe revealed clonal numerical abnormalities of chromosomes 11 and 14 in some cells. The detection of multiple abnormalities explains the bad prognosis in the present case. On the basis of our findings, we can easily conclude that results of cytogenetic analyses of similar mantle cell lymphoma patients would provide clues about new responsible gene regions and disease prognosis. In conclusion, it has been suggested that the presence of multiple chromosomal aberrations in addition to the specific t(11;14) may have a negative impact on clinical course and survival rate.

Pathology Consultation on Intermediate-to-Large B-Cell Lymphomas

Intermediate-to-large B-cell lymphomas represent a heterogeneous group of aggressive lesions frequently encountered in practice. The differential diagnosis includes the most common of all lymphomas, diffuse large B-cell lymphoma (DLBCL), as well as Burkitt lymphoma (BL), B-lymphoblastic lymphoma, and the blastoid variant of mantle cell lymphoma. In recent decades, gene expression profiling studies have clarified the biologic origins and features of these diseases. Moreover, clinically relevant subtypes of DLBCL have been identified, and a new category was defined: B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and BL. Herein, we review the salient diagnostic features of the various entities within this differential diagnosis and provide a stepwise diagnostic approach for dealing with challenging cases. A case-based approach is used to highlight diagnostic dilemmas and clinical decision points within the differential diagnosis of intermediate-to-large B-cell lymphomas. Based on the published literature and World Health Organization criteria, we suggest a diagnostic algorithm for appropriate classification of these lymphomas. Correct classification of intermediate-to-large B-cell lymphomas is important, because prognosis and therapeutic approach vary for different tumors and tumor subclasses. Understanding both disease-specific criteria and pathologic features that influence clinical behavior within a category is imperative for evaluation of these lymphomas.

Blastoid Variant of Mantle Cell Lymphoma- a Rare Case Report

Mantle cell lymphoma is now recognised as a rare but distinct entity in the revised WHO classification. It is now well recognised that MCL represent a broad spectrum of different histopathological subtypes. The term blastic or blastoid variant is generally used to describe cases with a homogeneous population of cells displaying lymphoblastic morphology. The blastic form of MCL may be difficult to diagnose however immunophenotyping and molecular analysis show typical mantle cell lymphoma pattern. We present a case of 30 year old male presenting with inguinal mass which was diagnosed as blastic transformation of mantle cell lymphoma based on routine histopathology and immunohistochemistry.

Mantle Cell Lymphoma of Blastoid Variant With Skin Lesion and Rapid Progression

Mantle cell lymphoma (MCL) is a type of aggressive mature B-cell neoplasm. Skin involvement of MCL is extremely rare, with only 21 cases reported so far. We report a case of MCL with blastoid variant, presenting as skin lesion initially. A 53-year-old man presented with increasing petechiae and ecchymosis after slight hit. Biopsy of skin showed tumor cells densely infiltrated dermal and subcutis with blastoid cytological features and numerous mitotic figures. Immunohistochemistry study showed tumor cells were positive for CD20, CD79a, BCL2, CyclinD1, and MUM1 but lost CD5 expression. Fluorescence in situ hybridization (FISH) studies demonstrated t(11;14). Although received chemotherapy after the diagnosis established, the patient deteriorated rapidly and died 5 weeks after presenting with skin lesions.

A rare case of leukemic presentation of blastoid variant of mantle cell lymphoma with isolated splenic involvement: Flowcytometric revelation

Mantle cell lymphoma (MCL) is a B-cell neoplasm generally composed of monomorphic, small to medium-sized lymphoid cells with irregular nuclear contours and a CCND1 translocation. It comprises approximately 3–10% of non-Hodgkin lymphomas and occurs in middle-aged to older individuals with a median age of about 60 years and a variably marked male predominance (about 2:1 or greater). Lymph nodes are the most commonly involved site; spleen and bone marrow (BM), with or without peripheral blood (PBS) are the other frequently involved extranodal sites.1 Classical MCL is a monomorphic lymphoid proliferation with a vaguely nodular, diffuse, mantle zone or rarely follicular growth pattern. One of the variant is blastoid variant which is considered to be more aggressive and characterized by the cells which resemble lymphoblasts with dispersed chromatin and a high mitotic rate.1 The peripheral spill with massive spleen is frequently seen in the classical MCL and splenic marginal zone lymphoma where differential diagnosis is splenic lymphoma with villous lymphocytes, Hairy cell leukemia and Small lymphocytic lymphoma (SLL)/Chronic lymphocytic Leukemia (CLL). The differentiation is done on the basis of flowcytometry. They are usually positive for CD5, FMC-7 and CD 43, but negative for CD10 and BCL6. These cells express relatively intense surface IgM/lgD, more frequently with lambda than kappa restriction. CD23 is negative or weakly positive. Aberrant phenotypes have been described, sometimes in association with blastoid/pleomorphic variants, including absence of CD5 and expression of CD43 and BCL6. All cases are BCL2 protein positive and almost all express cyclin D1, including the minority of cases that are CD5 negative. Leukemic presentation of B-MCL is an exceedingly uncommon event. Largest case series of 23 cases is published so far however, from India there is only one case which has been reported to best of our knowledge.2,3

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

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.

Mantle cell lymphoma with a unique pattern of CD5 expression: a case report with review of the literatures

Mantle cell lymphoma (MCL) is a unique subtype of B-cell non-Hodgkin's lymphoma characterized by chromosomal translocation t(11;14)(q13;q32), positive CD5, and nuclear cyclin D1 overexpression with unfavorable prognosis. We report herein a case of MCL in a 73-year-old male diagnosed with diffuse large B-cell lymphoma (ileal tumor) at another hospital, who subsequently relapsed with CD5-negative MCL. At the 1st relapse, he developed neck lymph node swelling, of which biopsy showed proliferation of atypical large pleomorphic cells with CD5-negativity by both immunohistochemistry and flow cytometry. At the 2nd relapse, he again developed an ileal tumor, of which biopsy showed positivity for CD5, CD20, and cyclin D1. In MCL, CD5-negative expression has sometimes been reported as having pleomorphic and blastoid variants. The present case was also histologically the pleomorphic type, but the CD5 expression changed from negative at the onset and the 1st relapse to positive at the 2nd relapse. This is a rare and interesting case because of the different expression of CD5 at all stage. This phenomenon made the diagnosis of MCL difficult.

Diagnosis of Mantle Cell Lymphoma, Blastoid Variant by Fine Needle Aspiration

Diagnosis of Mantle Cell Lymphoma, Blastoid Variant by Fine Needle Aspiration

Class IA Phosphatidylinositol 3-Kinase Inhibition Inhibits Cell Growth and Proliferation in Mantle Cell Lymphoma

Background/Aims: Constitutive activation of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin signaling pathway preferentially occurs in aggressive blastoid variants of mantle cell lymphoma (MCL) and is implicated in the pathogenesis of this disease. In this study, we investigated the role of PI3K isoforms on proliferation of aggressive MCL cells. Methods: The changes in cell viability, cell cycle distribution and apoptosis induction by the PI3K isoform-selective inhibitors were evaluated. The molecular basis underlying the effects of the specific inhibition of PI3K isoforms was investigated by Western blot analysis. Results: Our results demonstrated that a class IA PI3K isoform is most commonly involved in the constitutive activation of Akt in aggressive MCL. Treatment with a p110α isoform-specific inhibitor induced prominent cell cycle arrest followed by apoptosis through complete abolishment of phosphorylated (p)-Akt and its downstream targets. An inhibitor of isoform p110δ induced moderate cell cycle arrest with downregulation of p-Akt and p-S6K. A dual inhibitor of p110α and p110δ GDC-0941 caused more prominent cell growth inhibition compared to selective p110α or p110δ inhibitors. Inhibition of the class IB PI3K isoform p110γ did not cause cell cycle arrest or induce apoptosis in MCL cells. Conclusion: These findings suggest that the therapeutic ablation of class IA PI3K may be a promising strategy for the treatment of refractory, aggressive MCL.

Multiple Lymphomatous Polyposis Form of Blastoid Variant of Mantle Cell Lymphoma in Colon: a Case Report and Review of Literature

Primary non-Hodgkin's lymphoma (NHL) of the gastrointestinal tract is the most common extranodal NHL and accounts for 4–20 % of all NHL. Primary gastrointestinal lymphoma is most frequently diagnosed in the stomach and less frequently in the colon. Primary colorectal lymphomas are very uncommon, accounting for only 0.2 % of large intestinal malignancies [1, 2]. Multiple lymphomatous polyposis (MLP) is an extremely rare form of primary gastrointestinal (GI) lymphoma, which is characterized by multiple polyps formed by neoplastic lymphoid cells. It was for the first time described in 1961 by Cornes, and till now, approximately 70 detailed cases have been reported in the literature [3, 4]. Most of the MLP arise from the mantle cell lymphoma, whereas the rest originate from mucosal-associated lymphoid tissue (MALT) lymphoma or follicular lymphoma. The blastoid variant of mantle cell lymphoma has blastoid cytology with round to oval, large nuclei along with prominent nucleoli, in contrast to the much more common classic mantle cell lymphoma, having smallto medium-sized nuclei with irregular nuclear contours. Most of the cases that have been presented in literature are classic mantle cell lymphoma with typical cytology and low proliferation index [1–5]. Case Presentation

XVI. CNS prophylaxis in aggressive lymphomas: for whom and how

Dissemination in the central nervous system (CNS) in patients with aggressive lymphoma is a relatively rare but a frequently deadly complication that occurs between 5 (diffuse large B-cell lymphoma, DLBCL) and 30% (Burk itt lymphoma, BL and B-cell lymphoblastic lymphoma, B-LL) [1] in different subtypes of non-Hodgkin lymphoma (NHL). However, although a CNS prophylaxis is normally included into treatment regimens for BL and B-LL, in other NHL a prophylactic treatment is not systematically warranted because it may increase the toxicity of systemic chemotherapy.

Unusual concomitant rearrangements of Cyclin D1 and MYC genes in blastoid variant of mantle cell lymphoma: Case report and review of literature

We report herein a case of blastoid variant mantle cell lymphoma (MCL) with both aberrant phenotype and unusual genetics. Unexpectedly, lymphoma cells were CD5− and CD10+. Standard karyotype and FISH techniques showed that tumor cells carried two distinct translocations which had not been reported together in a same tumor. The first translocation juxtaposed the immunoglobulin lambda light chain locus with CCND1 locus, leading to Cyclin D1 overexpression. The second translocation revealed MYC rearrangement with a non-immunoglobulin gene partner located on the short arm of chromosome 4. The interpretation of the case on tissue sections alone could have been challenging. Indeed, the lack of CD5 and expression of CD10 associated with MYC rearrangement detected on interphasic nuclei could support the diagnosis of diffuse large B-cell lymphoma or Burkitt lymphoma. This distinction is also especially important as these lymphoma subtypes require specific treatment.

Aggressive B-cell lymphomas: how many categories do we need?

Aggressive B-cell lymphomas are diverse group of neoplasms that arise at different stages of B-cell development and by various mechanisms of neoplastic transformation. The aggressive B-cell lymphomas include many types, subtypes and variants of diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL), mantle cell lymphoma and its blastoid variant, and B lymphoblastic lymphoma. Differences in histology, cytogenetic and molecular abnormalities, as well as the relationship with the tumor microenvironment, help define characteristic signatures for these neoplasms, and in turn dictate potential therapeutic targets. Rather than survey the entire spectrum of aggressive B-cell lymphomas, this report aims to identify and characterize important clinically aggressive subtypes of DLBCL, and explore the relationship of DLBCL to BL and the gray zone between them (B-cell lymphoma unclassifiable with features intermediate between DLBCL and BL).

Fatal Blastoid Variant Mantle Cell Lymphoma in a Patient with Sjögren's Syndrome

Primary Sjögren's syndrome (pSS) is an autoimmune disorder of the exocrine glands presenting with progressive ocular and oral dryness, parotid gland enlargement, and often with extraglandular manifestations. In this group of patients the risk of development of non-Hodgkin's lymphoma is 16-fold compared to healthy population, mainly of the MALT lymphoma type. This case reports a 52-year-old woman with pSS developing a progressively growing mass at face and neck compatible with blastoid variant mantle cell lymphoma and a fatal outcome.

Clinical, Metabolic and Molecular Responses After 4 Courses of R-DHAP and After Autologous Stem Cell Transplantation for Untreated Mantle Cell Lymphoma Patients Included in the LyMa Trial, a Lysa Study

AbstractAbstract 152Mantle cell lymphoma (MCL) is a rare B-cell malignancy characterized by the t(11;14) translocation. The European MCL network has demonstrated that a sequential R-CHOP/R-DHAP chemotherapy regimen prior to autologous stem cell transplantation (ASCT) provides better disease control than R-CHOP (Hermine et al, ASH 2010, abstract 110) and that molecular minimal residual disease (MRD) measured by IGH real-time quantitative polymerase chain reaction (PCR) before and after ASCT is an important prognostic factor to predict progression-free survival (PFS) (Pott et al. Blood. 2010;115(16):3215–23). Indeed, the use of high-dose aracytine upfront before ASCT is now recommended and molecular remission appears to be a major objective for future clinical trials in MCL. It therefore appeared interesting to appreciate response rates combining standard evaluation (Cheson 1999), FDG-PET imaging (Cheson 2007) and PCR techniques after rituximab plus upfront high-dose aracytine (R-DHAP) followed by ASCT. Response rates after 4 courses of R-DHAP were one of the objectives of the LyMa trial (NCT00921414). This trial is a randomized, open-label, phase III study that evaluates the efficacy of rituximab maintenance therapy in MCL patients aged between 18 and 66 years old, undergoing first-line treatment with 4xR-DHAP and exhibiting a response after ASCT (R-BEAM). Patients who do not reach a sufficient partial remission after R-DHAP are planned to receive 4 additional courses of R-CHOP before ASCT. The LyMa trial started in September 2008 and was designed to enroll 299 patients over a 4 years period. To date (August 2012), 295 patients have been included. Herein, we report response rates according to the combination of Cheson 1999 and 2007 criteria plus molecular response rates after 4xR-DHAP and after ASCT for the first 200 enrolled patients (last inclusion in August 2011). Results:One patient withdrew consent and the analysis is therefore on 199 patients. The cohort’s median age is 57.2 years (range 29.7–65.7) and 41 patients are female (20%). At diagnosis, simplified MIPI was low in 104 cases (52%), intermediate in 55 (28%) and high in 40 (20%).Twenty-five patients (12.5%) presented with a blastoid variant. The panel of pathologist experts confirmed the diagnosis in all reviewed cases. Among the 199 evaluable patients, 182 (91%) received 4 courses of R-DHAP and 12 patients (all in PR according to Cheson 99 criteria) received 4 additional courses of R-CHOP because of insufficient clinical response after R-DHAP. Among these 12 patients, 5 reached CR/CRu after R-CHOP. Ultimately, 164 patients (82%) proceeded to ASCT (158 after R-DHAP and 6 after RDHAP/R-CHOP) and 154 (77.4%) have been randomized between rituximab maintenance or no maintenance. In an intention-to-treat (ITT) analysis and according to Cheson 1999 criteria, 152 patients (76.3%) reached CR (n=74) or CRu (n=78) after 4 courses of R-DHAP while 25 patients reached PR and 8 presented with SD/Prog. According to Cheson 2007 criteria (n= 170; PET not done in 17 cases and data missing in 12 cases), 129 patients reached CR while 41 patients remained FDG-TEP positive. Response rates according to Cheson 1999 and 2007 criteria for transplanted patients (n=164) were CR (n=109)/CRu (n=45) in 94% and CR in 84.5% (129 patients underwent FDG-PET after ASCT), respectively. Regarding MRD, diagnosis samples were available for 186/199 patients. Forty-one diagnosis samples have not yet been analyzed and 14 proved to be not informative. To date, the molecular response on peripheral blood (PB) after 4 courses of R-DHAP has been assessed in 103 cases and found negative in 80 cases and positive in 22 cases (not evaluable in one case). MRD on bone marrow (BM) after 4 courses of R-DHAP has been measured in 97 cases and found negative in 59 and positive in 36 (not evaluable in one case). After ASCT, PB and BM MRD were found negative in 91 patients (95 samples have been analyzed to date) and 67 (87 samples analyzed), respectively. Thus, in the LyMa trial,CR/CRu rates after only 4 courses of RDHAP, according to Cheson 1999 and 2007 criteria, are very high confirming the major anti-tumoral impact of high-dose aracytine upfront in MCL. In addition, these encouraging results seem to be confirmed at the molecular level strengthening the interest of an MRD-guided management of MCL patients. Results will be updated at the time of the meeting and patients’ outcome according to disease status will be presented. Disclosures:Ribrag:Servier: Membership on an entity’s Board of Directors or advisory committees, Research Funding; AstraZeneca: Membership on an entity’s Board of Directors or advisory committees; Takeda: Membership on an entity’s Board of Directors or advisory committees; Bayer: Research Funding; Sanofi-Aventis: Research Funding; Johnson & Johnson: Membership on an entity’s Board of Directors or advisory committees.

Autologous and Allogeneic Donor Transplantation for Mantle Cell Lymphoma in Rituximab Era: Impact of Pre-Transplant Burden On Survival.

AbstractAbstract 3092▪▪This icon denotes a clinically relevant abstractThe survival for patients with mantle cell lymphoma (MCL) can be prolonged by the use of rituximab-containing intensive chemotherapies and hematopoietic cell transplantation (HCT). However, the optimal application of autologous and allogeneic HCT in the rituximab era remains uncertain.We report 66 patients with MCL who underwent HCT (38 autologous and 28 allogeneic) at the University of Minnesota between 1999–2010. Eighty eight percent received a Rituximab-containing induction chemotherapy. Autologous HCT patients were older (66% were ≥60 years of age), 70% were in CR1 and all except 1 were chemosensitive. Two patients had minimal residual disease in the marrow (MRD) and two-thirds were PET negative at the time of transplant. Allogeneic HCT patients were younger (85% were <60 years old), 19% were in CR1 and 21% had chemo-resistant disease. At the time of transplant, 80% of allogeneic patients were PET positive and 18% of patients had detectable marrow MCL. Allogeneic recipients had a significantly longer time from diagnosis to transplant (allo 17.7 months vs auto 7.6 months; p≤0.01).At a median follow-up of 3.5 years (range 1.1–9.2 years), the 5-year disease free survival (DFS) and overall survival (OS) of the autologous cohort were 59% and 62%, respectively (Table). In univariate analyses for DFS, younger age, absence of splenic and extranodal disease at diagnosis and shorter time to transplant were significantly associated with better survival (age <60 vs. ≥60 yrs 92% [95 CI 57–99%] vs. 43%[95 CI 18–66%]; p=0.04; extra nodal disease positive 25% [95 CI 2–63%] vs negative 77% [95 CI 48–91%]); p=.02; diagnosis to HCT time <8 months vs. ≥8 months 79% [95 CI 51–92%] vs 32% [95 CI 7–62%]; p=0.03). Patients with residual disease pre auto HCT (PET scan + and/or MRD) had significantly worse DFS (residual disease positive: 46% (95 CI 14–73%) vs negative 68% (95 CI 33–87%); p=0.04). The type of induction chemotherapy, disease status (CR1 vs other), blastoid variant or comorbidity index did not impact DFS or OS. The cumulative incidence of relapse and treatment related mortality (TRM) are shown. Notably, none of the patients with negative pre auto- transplant PET scan and lack of MRD relapsed at 2 years (p=<.01). In multivariate analysis, residual lymphoma (by PET or MRD pos) was the single significant factor associated with 5-fold lower rate of DFS compared to no residual disease (HR: 5.26 (96% CI 1.17–23.55); p=0.03).Twenty-eight patients received allogeneic transplants (17 sibling donor, 10 umbilical cord blood, 1 unrelated donor). Half were transplanted using a reduced intensity conditioning (RIC) regimen and five patients failed a prior autograft. At a median follow-up of 6.7 years (range 1–10.3 years), the 5-year DFS and OS were 34% and 52%, respectively (Table). In univariate analysis the 5 year DFS was not significantly affected by chemosensitivity, disease status, PET positivity or MRD prior to transplant (Chemo sensitive: 41% (95 CI 20–61%) vs. resistant 17% (95 CI 1–52%) p=.38; CR1/PR1 40% (95 CI 5–75%), resistant 17% (95 CI 1–52%%), relapse 42% (95 CI 18–65) p=.66; PET pos 33% (95 CI 10–59%) vs PET neg 67% (95 CI 5–95%) p=.63). DFS following myeloablative (MA) conditioning was similar to that of RIC (43% [95 CI 16–68%] vs. 27% [95 CI 8–50%]; p=.57); MRD not shown). OS was not significantly affected by PET or marrow status prior to HCT. The cumulative incidence of 2 year relapse and 1 year TRM are shown. No relapses occurred in the MA cohort compared to a 29% relapse rate (95 CI 6–53%) after RIC HCT (p=.08). Conversely, 2 year TRM for allograft recipients was 2 times higher with MA conditioning (33% (95 CI 7–59%) compared to RIC (15% (95 CI 0–32%); p=.29).Survival of MCL patients post autologous and allogeneic HCT has improved in the last decade. Long-term disease control is observed following autologous HCT in CR1 or for relapsed MCL, particularly if a PET negative state can be attained pre-transplant. Patients with more advanced disease and higher MCL burden prior to HCT can benefit from allogeneic transplantation. Novel therapies designed to better control MCL pre-transplant and to reduce post-transplant relapse after RIC HCT may further improve survival.Transplant Type5 yr DFS (95% CI)5yr OS (95% CI)2 yr Relapse (95% CI)1 yr TRM (95% CI)Autologous59% (37-76%)62% (39-79%)14% (3-24%)5% (0-12%)Allogeneic34% (17-51%)52% (32-69%)25% (8-43%)19% (4-34%) Disclosures:No relevant conflicts of interest to declare.

Population Survey of Mantle Cell Lymphoma (MCL) in British Columbia (BC) – A Heterogeneous Disorder with Improved Outcomes in the Modern Era

Abstract 1602 Introduction: MCL presents a therapeutic challenge remaining incurable with standard therapy. Most pts exhibit aggressive behaving advanced (adv) stage disease at diagnosis and require multi-agent chemotherapy, while others may have an indolent course. Improved outcomes with rituximab (R) and autologous stem cell transplant (ASCT) have been reported for select pts within the context of small clinical trials. In the province of BC, a new policy was introduced in 2003 recommending upfront ASCT for all eligible pts with adv stage MCL. This largely coincided with the availability of R which was included in the protocol: 6 cycles R-CHOP induction followed by ASCT and 2 cycles R maintenance (R weekly × 4 at 2 and 6 mo). The aim of this study was to review the clinical profile of MCL within a non-selected population of pts and to evaluate outcomes before and after this policy change. Methods: Using the BC Cancer Agency Centre for Lymphoid Cancer database, we identified all pts diagnosed with MCL between Jan 1990 and Dec 2010. Pathology was centrally reviewed and clinical data was retrieved from the database and medical records. Within this grp, we identified a SCT eligible cohort (<66 y with adv stage, excluding pts initially observed) and outcomes were evaluated in the pre and post SCT era, based on the policy initiation date of Jan 2003. Results: In total 535 pts were identified, median age 67 y (range 22–94), 71% male, 88% adv stage, 8% limited (lim) stage (stage I/II, bulk 10 y), mainly diagnosed prior to SCT policy (where f/up is shorter) and were treated with various regimens. Within this grp, median age was 57 y and 28% had lim stage, but no obvious associated clinical parameters were noted. To evaluate the impact of initial SCT, we compared outcomes in SCT eligible pts (n=179), diagnosed prior to (pre-SCT, n=93) and following its introduction in 2003 (post-SCT, n=86). Clinical characteristics were comparable between the pre-SCT and post-SCT grps; median age 56 y, MIPI score 20% high, 28% intermed, 52% low. Within the pre-SCT grp, initial treatment included CHOP-like chemo (n=46), intensive chemo (n=20), non-anthracycline-based tx (n=20) and SCT (n=3, 1 allo; received prior to policy initiation), median f/up 11 y. Within the post-SCT grp, initial treatment included SCT (n=50, 2 allo), CHOP-like chemo (n=31), non-anthracycline-based tx (n=5), median f/up 4.4 y. Thirty-six post-SCT pts did not undergo SCT (13 co-morbidities, 13 progressive disease during induction, 6 unknown/not offered, 4 declined). R was received by 8/93 (9%) pre-SCT pts and 81/86 (94%) post-SCT pts. Based on era of treatment, outcomes were significantly improved in the post-SCT grp compared with the pre-SCT grp, median OS not reached v 3.4 y, p=0.001 (5-y OS 58% v 34%) and median PFS 3.5 y v 1.3 y, p<0.001 (5-y PFS 38% v 16%). (see figure) An analysis based on actual initial treatment received (SCT v no-SCT), demonstrates favorable outcome associated with SCT (5-y OS 78% v 31%; 5-y PFS 55% v 15%). Conclusion: Outcomes for MCL have significantly improved in the modern era following the introduction of upfront ASCT in BC. Availability of rituximab coincided with this policy change and likely contributed to this improvement. Similar to prior observations, a subset of pts with indolent behaving disease can be observed without impacting OS. Patients with limited stage disease have a more favorable outcome, but no survival plateau was noted. ![Figure][1] ![Figure][1] Disclosures: den Brok: F Hoffmann-La Roche (Roche Canada): Consultancy, Research Funding. Song: F Hoffmann-La Roche (Roche Canada): Consultancy, Research Funding. OLeary: F Hoffmann-La Roche (Roche Canada): Consultancy, Research Funding. Klasa: F Hoffmann-La Roche (Roche Canada): Consultancy, Research Funding. Savage: Roche: Research Funding. Shenkier: F Hoffmann-La Roche (Roche Canada): Consultancy, Research Funding. Villa: F Hoffmann-La Roche (Roche Canada): Consultancy, Research Funding. Slack: F Hoffmann-La Roche (Roche Canada): Consultancy, Research Funding. Shepherd: F Hoffmann-La Roche (Roche Canada): Consultancy, Research Funding. Gascoyne: F Hoffmann-La Roche (Roche Canada): Consultancy, Research Funding. Connors: F Hoffmann-La Roche (Roche Canada): Consultancy, Research Funding. Sehn: F. Hoffmann-La Roche (Roche Canada): Research Funding. [1]: pending:yes

Microrna-16 Regulates BMI1 in the Clonogenic Side Population of Refractory Mantle Cell Lymphoma

AbstractAbstract 861 Background:Mantle cell lymphoma (MCL) is categorized as an indolent CD5+ B-cell lymphoma and is associated with numerous genomic copy number alterations, including 9p21 deletion (CDKN2A) and 10p12 amplification (BMI1). The target gene of the 10p12 amplification has been identified as BMI1, whose overexpression is frequently observed in the blastoid variant of MCL. CDKN2A is also well-known target of BMI1 in solid tumor. So, it has been hypothesized that BMI1 regulates CDKN2A in MCL. However there are the MCL cases with both 10p12 amplification and 9p21 homozygous deletion, suggesting that BMI1 might regulate the other target gene(s). The proto-oncogene, BMI1 is crucially involved in cancer stem cell maintenance and the upregulation has been demonstrated in aggressive or relapsed cases of solid tumors. Cancer stem cells are often identified in the side population (SP) of cancer cells, which is detected based on the cell's ability to export Hoechst 33342 dye via an ATP-binding cassette (ABC) membrane transporter, which gives the SP a distinct low-staining pattern. Aim of the study:The aim of this study is to determine the role of BMI1 in MCL initiating cells, especially in the relapsed cases. In this presentation, we show that the SP fraction has stem cell-like characteristics and high tumorigenic potential, and that BMI1 expression is upregulated in the SP in both relapsed MCL cases and MCL cell lines. Further we show that miR-16 is upstream regulator of the BMI1 in MCL. Results:To determine the role of BMI1 in the pathogenesis of MCL-initiating cells, we firstly examined BMI1 expression at primary MCL cases and found that its expression is stronger in cases of recurrent MCL than at initial diagnosis. We next characterized the MCL SP and found that the SP cells exhibit cancer stem cell-like features and upregulated BMI1 expression, which appears to enhance anti-apoptosis activity. Knocking down of BMI1 increases apoptosis and reduces tumorigenicity in CDKN2A−/− MCL cell lines (REC1 and Z138c). Subcutaneous inoculation of NOD/Shi-scid IL-2γnul (NOG) mice with CDKN2A−/− MCL cell lines, siBMI1-expressing cells were significantly smaller than those in mice receiving control siRNA in vivo. Chip assay showed that BMI1 interacts with BCL2L11/Bim and PMAIP3/Noxa, which were recently shown to be Bmi-1 target. These results suggest that BMI1/Bmi-1 may regulate Bim and/or Noxa to inhibit apoptosis in MCL cells. Furthermore, upon screening for upstream regulator of BMI1, we found that expression of a non-cording regulatory RNA, microRNA-16 (miR-16) is weaker in MCL SP cells than in non-SP cells. To investigate relationship between BMI1 and miR-16, we transfected miR-16 into MCL cell lines, and found that it directly downregulated BMI1, leading to reductions in tumor size following in vivo lymphoma xenograft (NOG mice). Finally, we find that bortezomib, which is known to be a proteasome inhibitor, led to dose-and time- dependent reductions in Bmi-1 expression with re-upregulation of miR-16 in both cell lines and a primary sample. Conclusion:We conclude that dysregulation of miR-16 and BMI1 plays a key role in lymphomagenesis by reducing MCL cell apoptosis, especially in refractory/recurrent cases via enhancement of anti apoptotic function. Disclosures:No relevant conflicts of interest to declare.