Blastoid Variant Mantle Cell Lymphoma Research Articles

Blastoid Variant Mantle Cell Lymphoma with Amplified <i>IGH/CCND1</i> Fusion: A Unique Case and Current Literature Review

Blastoid Variant Mantle Cell Lymphoma with Amplified <i>IGH/CCND1</i> Fusion: A Unique Case and Current Literature Review

Blastoid variant mantle cell lymphoma with aberrant expression of CD10.

Blastoid variant mantle cell lymphoma with aberrant expression of CD10.

Characteristics of Patients with Observation As Initial Treatment Strategy in Mantle Cell Lymphoma

Background: Mantle cell lymphoma (MCL) is a type of non-Hodgkin lymphoma with a heterogenous clinical course and outcomes dependent on various clinical and biological prognostic factors. About 17% of MCL patients (pts) have an indolent course without the need to initiate treatment at diagnosis (Abrisqueta et al 2017). Therefore, our objective was to describe baseline characteristics of pts who received treatment more than 3 months after diagnosis (Observation) and contrast it with those who received treatment within 3 months of diagnosis (Early treatment) Methods: Data was collected from the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database. The Flatiron Health database is a longitudinal database, comprising de-identified patient-level structured and unstructured data, curated via technology-enabled abstraction. During the study period, the de-identified data originated from approximately 280 cancer clinics (~800 sites of care). Inclusion criteria included pts diagnosed with MCL between January 2011 to October 2021 and with a follow up of more than 1 year from the time of diagnosis with at least two visits documented in EHR. Patients who initiated any treatment within 90 days of diagnosis were the early treatment group while the remainder made up the observation group. Baseline variables including age, sex, practice type, disease subtype, Ann Arbor stage, presence of deletion of chromosome 17p, lactate dehydrogenase (LDH), WBC count, eastern co-operative oncology group (ECOG) performance status, Ki-67 and SOX11 staining were collected within 90 days of diagnosis. MIPI original score was calculated using the formula MIPI formula = [0.03535 × Age (years)] + 0.6978 (if ECOG 2-4) + [1.367 × log10(LDH/ULN)] + [0.9393 × log10(WBC)]. Kaplan Meier method was used to calculate real- world overall survival (rwOS) from the date of diagnosis and compared by log rank test between the two groups. Time to treatment initiation (TTTI) was defined as time from diagnosis to time of first treatment. Baseline characteristics between group were compared using chi square test or Kruskal-Wallis test. Results: Of 4336 patients, 3146 patients met inclusion criteria with 2346 patients (75%) receiving treatment within 3 months of diagnosis (early treatment group). The remaining 800 patients (25%) made up the observation group. Of these, 274 patients (34%) did not have any documented treatment. The median follow up duration for the entire group was 59 months (IQR 33 - 88).The baseline characteristics are as described in table 1. The median time to treatment initiation was 1 month (IQR 0.5 - 1.0) for the early treatment group versus 13 months (IQR 5 - 27) for the observation group. Compared with the early treatment group, the observation group was found to have a lower mean age and a higher proportion of patients with stage I/II disease (15% versus 9%), diagnosis made at an academic center (22% versus 14%), presence of deletion 17p (14 % versus 9%) and Ki67 staining < 30% (62% versus 39%). The early treatment group had higher proportions of patients with blastoid variant MCL (7% versus 2%) and SOX11 staining (81% versus 71%). The observation group showed a superior rwOS, with rwOS of 86 months (95%CI 83 - 99) for the observation group compared to 72 months (95%CI 68 - 77) for the early treatment group. Conclusions: Our study shows that approximately 25% of all newly diagnosed MCL did not receive immediate treatment, with a median time from diagnosis to treatment of 13 months for initially observed patients. These patients were older and had early-stage disease with a low Ki-67 index. Despite delayed treatment initiation, the rwOS for these patients was superior to that of patients who received immediate treatment. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Stem cell transplant for mantle cell lymphoma in Taiwan

Mantle cell lymphoma (MCL) is a B-cell lymphoma featuring an aggressive course and a progressive relapsing pattern. International guidelines recommend early consolidative autologous stem cell transplant (auto-SCT) for eligible patients while reserving allogeneic SCT (allo-SCT) as therapy for refractory cases. Since data describing the implementation of transplants in the Asian population with MCL are limited, we aimed to analyze post-SCT outcomes of 99 MCL patients from the Taiwan Bone Marrow Transplant Registry database. The median age was 56 years, and 11% of the patients had blastoid variant MCL. Ninety-four patients received auto-SCT, while 13 patients received allo-SCT, eight of which received allo-SCT after failing auto-SCT. Before auto-SCT, 52% of the patients were in their first complete remission (CR1). Overall, 37 patients (39%) relapsed after auto-SCT. The median post-auto-SCT progression-free survival and overall survival (OS) were 43.6 months and not reached, respectively. Blastoid variant MCL, transplant not received in CR1, and disease progression within 12 months post-auto-SCT independently predicted inferior OS in multivariable analysis. The median post-allo-SCT OS was 74 months. Two patients (15%) died of MCL recurrence post-allo-SCT. Three patients with refractory diseases were salvaged with ibrutinib or venetoclax to allo-SCT. Treatment strategies incorporating novel agents warrant further optimization.

Blastoid variant mantle cell lymphoma with aberrant expression of CD10.

Blastoid variant mantle cell lymphoma with aberrant expression of CD10.

CD5-negative blastoid variant mantle cell lymphoma: a diagnostic dilemma

We encountered two cases of CD5- blastoid variant mantle cell lymphoma (MCL), prompting us to investigate the proportion of CD5 negativity in MCL and assess the diagnosis of aggressive MCL variants. Among 117 patients diagnosed with MCL, CD5 negativity was observed in 13% (13/104) of cases with classical MCL and 15% (2/13) of cases with blastoid/pleomorphic variant MCL. Of the aggressive MCL variant cases, tumor cells exhibited intermediate nuclear size and required differential diagnosis between blastoid variant and classical MCL in six patients, and classical MCL cells were found in the background of aggressive variant tumors or in other sites in six patients. Of 1534 patients with diffuse large B-cell lymphoma (DLBCL), CD5 positivity was observed in 8% (121/1534) of cases. Immunohistochemical staining for cyclin D1 performed for these cases revealed one cyclin D1-positive and IGH/CCND1 fusion-positive case (0.9%, 1/114), namely pleomorphic variant MCL. Of the remaining 1413 patients initially diagnosed with CD5- DLBCL, the diagnoses of two patients (0.1%) were amended to CD5- blastoid variant MCL in the relapse phase based on morphology, cyclin D1 immunostaining, and fluorescence in situ hybridization. The incidence of CD5 negativity was similar between classical MCL and two aggressive variants. Accurate diagnosis of MCL variants was enabled by identifying a classical MCL component and/or CD5 positivity; however, we misdiagnosed two cases of CD5- blastoid variant MCL. A small number of MCL variants may be included in CD5- DLBCL cases. The diagnosis of CD5- aggressive variant MCL remains challenging but crucial because of its therapeutic significance.

Bi-allelic amplification of ATM gene in blastoid variant of mantle cell lymphoma: a novel mechanism of inactivation due to chromoanagenesis?

BackgroundMantle cell lymphoma (MCL) is derived from naïve CD5+ B-cells with the cytogenetic hallmark translocation 11;14. The presence of additional abnormalities is associated with blastoid variants in MCL (BMCL) and confers a poor prognosis. Many of these tumors also show deletion or loss of heterozygosity (LOH) of the ATM gene and biallelic ATM inactivation show significantly higher chromosomal imbalances.Case presentationHere we report a 52 year-old male who presented to the clinic with worsening dyspnea, fever, chills, diffuse lymphadenopathy, splenomegaly and leukocytosis with blastoid cells circulating in blood. The bone marrow aspirate showed about 40% abnormal blast-looking cells and biopsy revealed a remarkable lymphoid infiltrate. The patient was diagnosed with blastoid variant mantle cell lymphoma (BMCL). Chromosome analysis on bone marrow showed a complex karyotype. FISH analysis from B-cell lymphoma panel showed bi-allelic amplification of ATM gene. Other abnormalities were present including CCND1/IGH fusion, confirming the MCL diagnosis, in addition to RB1 and p53 deletion. High resolution SNP-microarray studies showed complex copy number changes, especially on chromosomes 7 and 11, consistent with chromoanagenesis. Microarray studies also showed LOH at the ATM locus indicating the amplification seen on FISH is not biallelic.ConclusionTo the best of our knowledge, ATM gene amplification is not previously reported in BMCL and our case suggests a novel mechanism of ATM inactivation caused by chromoanagenesis resulting in mutant allele specific imbalance with copy number gain.

Subcutaneous Epcoritamab Induces Complete Responses with an Encouraging Safety Profile across Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma Subtypes, Including Patients with Prior CAR-T Therapy: Updated Dose Escalation Data

Subcutaneous Epcoritamab Induces Complete Responses with an Encouraging Safety Profile across Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma Subtypes, Including Patients with Prior CAR-T Therapy: Updated Dose Escalation Data

Early Experience Using Radiotherapy As a Salvage Treatment for Relapsed or Refractory Non-Hodgkin Lymphomas Following CD19 Chimeric Antigen Receptor Modified T-Cell Therapy

Anti-CD19 chimeric antigen receptor modified T-cells (CAR T) produce remarkable responses for relapsed/refractory diffuse large B-cell lymphoma but over half of patients will relapse. Disease progression post CAR T therapy remains challenging and without standard guidelines. Radiotherapy is potentially an important salvage approach, but limited data exists to guide optimal utilization. We reviewed the first 15 patients treated with salvage radiotherapy (SRT) following CAR T progression. All but two patients had DLBCL; one had blastoid variant mantle cell lymphoma and the other patient was best classified as a CD5+ high grade lymphoma not otherwise specified. Outcomes included post RT response, freedom from subsequent relapse (FFSR) and overall survival (OS). Patients were heterogeneous and heavily-treated with a median of 4 prior lines of pre-CAR T therapy (range 2-8). Median time to first post-CAR T relapse was 82 days and RT was part of the first salvage regimen for 73%. Most received SRT to a site that was previously avid pre-CAR T. Post SRT, there were 6 evaluable patients with limited stage relapse; objective response rate was 100% (n=3 CR and n=3 PR). For advanced-stage relapse, while many had in-field PR, nearly all had concomitant out-of-field progression. Median OS from first post-CAR T relapse was 11 months. Patients with localized vs. advanced stage relapse had significantly improved FFSR (hazard ratio, HR=0.11, p=0.009) and OS (HR 0.10, p=0.003). By second-line age-adjusted IPI (sAA-IPI), 40% were low or low-intermediate risk and lower sAA-IPI risk prognosticated improved OS post SRT (p=0.004). Four patients were bridged to allogeneic transplantation with SRT and at analysis, 3 were alive and NED with 4.9, 7.2 and 36.2 months of post-allogeneic transplant follow-up. The fourth patient was also NED but deceased from transplant-related complications. SRT following CAR T is feasible with powerful and diverse utility including local palliation for transplant-ineligible patients. For lower risk and localized relapses, SRT may be integrated with novel targeted agents, immunotherapies or transplantation to attempt durable remissions. Disclosures Palomba: Hemedicus: Other: Immediate Family Member, Speakers Bureau ; Merck &amp; Co Inc.: Other: Immediate Family Member, Consultancy (includes expert testimony); Seres Therapeutics: Other: Immediate Family Member, Equity Ownership and Membership on an entity's Board of Directors or advisory committees; STRAXIMM: Other: Immediate Family Member, Membership on an entity's Board of Directors or advisory committees; Kite Pharmaceuticals: Other: Immediate Family Member, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Noble Insights: Consultancy; Evelo: Other: Immediate family member, Equity Ownership; MSK (IP for Juno and Seres): Other: Immediate Family Member, Patents &amp; Royalties - describe: intellectual property rights . Sauter:Novartis: Consultancy; Sanofi-Genzyme: Consultancy, Research Funding; Juno Therapeutics: Consultancy, Research Funding; GSK: Consultancy; Spectrum Pharmaceuticals: Consultancy; Genmab: Consultancy; Precision Biosciences: Consultancy; Celgene: Consultancy; Kite/Gilead: Consultancy. Scordo:Angiocrine Bioscience, Inc.: Consultancy; McKinsey &amp; Company: Consultancy. Batlevi:Juno Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Park:Allogene: Consultancy; Amgen: Consultancy; AstraZeneca: Consultancy; Autolus: Consultancy; GSK: Consultancy; Incyte: Consultancy; Kite Pharma: Consultancy; Novartis: Consultancy; Takeda: Consultancy. Shah:Janssen: Research Funding; Amgen: Research Funding. Giralt:Celgene: Consultancy, Research Funding; Takeda: Consultancy; Sanofi: Consultancy, Research Funding; Amgen: Consultancy, Research Funding. Perales:NexImmune: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; Medigene: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Kyte/Gilead: Research Funding; Miltenyi: Research Funding; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sadelain:Juno Therapeutics: Consultancy, Patents &amp; Royalties, Research Funding; Fate Therapeutics: Consultancy, Patents &amp; Royalties; Memorial Sloan Kettering Cancer Center: Employment.

Outcome of young patients with blastoid variant mantle cell lymphoma: An analysis of 138 patients.

e19548Background: Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma with heterogeneous outcomes. Small studies have shown that the blastoid variant has a particularly poor prognosis. We p...

Clinicopathologic Features, Management and Outcomes of Blastoid Variant (BV) of Mantle Cell Lymphoma (MCL): A Nebraska Lymphoma Study Group (NLSG) Experience

Background: Prior studies have demonstrated unique clinicopathologic features of the BV of MCL including an inferior response to chemotherapy and poor long-term outcomes as compared to other MCL variants in the pre-rituximab era. A paucity of data precludes whether the use of rituximab or intensified therapy can overcome the inferior outcome associated with the BV.Methods MCL patients (n=169) treated by NLSG between 1983 and 2010 were included. Morphologic variants were classified based on published WHO criteria. We compared disease characteristics, therapy and outcomes according to MCL subtypes using the Kruskal Wallis or Chi-square tests. Univariate probabilities of progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan Meier method. Multivariate analyses were performed using Cox proportional hazards regression to evaluate differences in outcomes of MCL subtypes while adjusting for prognostic covariates.Results The study population included 19% BV, 37% diffuse and 44% nodular subtypes. BV, diffuse and nodular subtypes differed in the median age (61 vs. 68 vs. 59, p=.002) and stage III/IV disease (81% vs. 79% vs. 93%, p=.05) at diagnosis, but did not differ in the distribution of sex, Karnofsky performance status (KPS), MCL international prognostic index (MIPI), lactate dehydrogenase (LDH) level, B-symptoms, or extranodal involvement. Patients received the following therapies: intensified therapy such as Cyclophosphamide, Vincristine, Doxorubicin, and Dexamethasone (Hyper-CVAD) +/- Rituximab (R) (30%), Cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-R-like (24%), CHOP-like (35%) or others (11%). Approximately one-third received autologous (25%) or allogeneic (8%) SCT. There was a significant difference in the type of chemotherapy given in each group (p=.002) but not in the use of radiation therapy or proportion in each group receiving autologous/allogeneic stem cell transplant (SCT). Median follow-up across MCL subtypes was similar. Overall response rate was similar for BV, diffuse and nodular subtypes (68% vs. 65% vs. 80%, p=.44). The 5-year progression-free survival for BV vs. diffuse vs. nodular was 16% vs. 22% vs. 31%; p=.06, (Figure 1) and 5-year OS was 24% vs. 32% vs. 56% respectively; p=.005, (Figure 2). In multivariate analysis, compared to BV, diffuse subtype had similar risk of disease progression or death (hazard ratio, HR of 0.78, 95% confidence interval (CI) of 0.48-1.26) whereas nodular subtype had lower risk (HR 0.62, 95% CI 0.39-0.99). Additionally, low or intermediate MIPI, good KPS, absence of B-symptoms and undergoing SCT were associated with lower risk of progression or death. A subset univariate analysis of BV demonstrated no survivors beyond 5 years after conventional chemotherapy, whereas 33% remained alive at 10 years after intensified therapy.Conclusions BV and nodular MCL presented at a somewhat younger median age compared to diffuse MCL, and BV and diffuse MCL was more likely to present as stage I/II disease, compared to nodular MCL. The PFS and OS of BV MCL are similar to diffuse MCL but OS is worse than nodular MCL. The use of SCT may improve survival in MCL including BV variant. [Display omitted] [Display omitted] DisclosuresArmitage:Ziopharm Oncology: Consultancy; GlaxoSmithKline: Consultancy; Spectrum Pharmaceuticals: Consultancy; Roche: Consultancy; Tesaro bio Inc: Membership on an entity’s Board of Directors or advisory committees.

Observational Study Alternating R-CHOP21 and R-Cytarabine (3+3 Cycles) for Patients with Newly Diagnosed Mantle Cell Lymphoma Not Eligible for High-Dose Therapy: A Czech Lymphoma Study Group Trial Preliminary Results

Abstract Background: Mantle cell lymphoma (MCL) is an aggressive type of B-cell non-Hodgkin lymphoma characterized by frequent relapses and adverse prognosis. Implementation of high-dose cytarabine (HDAC) and incorporation of anti-CD20 antibody rituximab (R) into induction and maintenance, and consolidation with high-dose therapy and autologous stem cell transplantation (HDT-ASCT) significantly improved pt´s outcome. Therapy of the elderly or comorbid (not eligible for HDT-ASCT) is largely based on R-CHOP or R-bendamustin induction with or without R maintenance. Minimal residual disease (MRD) assessment by quantitative PCR (qPCR) from peripheral blood or bone marrow (BM) has emerged as a powerful molecular marker of outcome. Based on the results of the younger pts some centers adopted the use of HDAC in elderly as well, but no data has been presented yet. Aim: We initiated the observational study as a non-intervention, multi-center trial with the primary objectives to prospectively evaluate efficacy of alternating R-CHOP21 and R-HDAC (1 or 2 g / m2, 2 doses a 24 hours) in newly diagnosed MCL pts not eligible for HDT-ASCT. Methods: Primary endpoints were overall response rate (ORR) by PET-CT, and MRD assessment by qPCR after completion of induction. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity. The choice between 1 and 2 g / m2 cytarabine was left at investigator´s discretion, as well as the rituximab maintenance. Patients with known cardiac co-morbidity could be treated with R-COEP (etoposid 50 mg / m2, D1-D3) instead of R-CHOP. Exclusion criteria included eligibility to HDT-ASCT, ECOG≥ 4, and CNS involvement. Results: Altogether 61 pts (38 men and 23 women, ratio 1.7:1) were enrolled into the study between 16-JUN-2011 and 18-MAR-2014. Median age was 70 years both for men and women. 91.5%, and 80% pts presented with stage 3/4 disease, and infiltration of BM, resp. According to the MIPI, 55.7%, 39.4%, and 4.9% pts had high, intermediate and low risk disease, resp. B-symptoms were recorded in 33.3% of pts. 76.8% and 24.2% pts were diagnosed from the lymph node, and trephine biopsy, resp. 62.8%, 27.9%, and 9.3% pts presented with classical, pleomorphic and blastoid variant MCL, resp. Ki67/MIB1 ≥ 30% was observed in 38% of pts. Bulky disease &gt;5cm, and &gt;10cm, was noticed in 31% and 13% pts. Spleen involvement was observed in 53% pts. Extra-nodal involvement other than BM was histologically confirmed in 11.5% pts. R-CHOP was used in 88% pts (12% pts received R-COEP), 86% pts received 2g / m2 cytarabine (14% pts 1g / m2). 86.3% pts with response were treated with R maintenace. Only one patient was excluded from the study due to unacceptable toxicity. 57.7% pts developed grade 3/4 hematologic toxicity (neutropenia, anemia or thrombocytopenia). Grade 3/4 non-hematologic toxicity occurred in 27.3% pts. All pts had PET-CT restaging after completion of induction. Overall response rate (CR+PR) reached 91.7%. CR and PR rate by PET was 76.7%, and 15%, resp. SD, and progression on therapy was noticed in 3.3%, and 5.0%, resp. Samples for MRD assessment were collected from 41 out of 54 pts, who completed induction and achieved response (CR or PR). At the time of abstract submission 21, 7, and 7 (out of 36 so far evaluated pts) were MRD negative, MRD positive-not quantifiable, and MRD positive-quantifiable, resp. With the median follow-up 19.1 month, there were 7 progressions and 6 deaths. 2-year PFS and OS probability were 83.9% and 88.1%. Conclusion: Alternation of R-CHOP and R-HDAC in newly diagnosed elderly or co-morbid MCL pts represents a promising, very effective and well-tolerated treatment approach that induces high ORR, and MRD negativity. Grant Support: IGA-MZ NT/13072-4, PRVOUK-27/LF1/1 Disclosures No relevant conflicts of interest to declare.

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.

NKT Cell Responses to B Cell Lymphoma

Natural killer T (NKT) cells are a unique subset of CD1d-restricted T lymphocytes that express characteristics of both T cells and natural killer cells. NKT cells mediate tumor immune-surveillance; however, NKT cells are numerically reduced and functionally impaired in lymphoma patients. Many hematologic malignancies express CD1d molecules and co-stimulatory proteins needed to induce anti-tumor immunity by NKT cells, yet most tumors are poorly immunogenic. In this study, we sought to investigate NKT cell responses to B cell lymphoma. In the presence of exogenous antigen, both mouse and human NKT cell lines produce cytokines following stimulation by B cell lymphoma lines. NKT cell populations were examined ex vivo in mouse models of spontaneous B cell lymphoma, and it was found that during early stages, NKT cell responses were enhanced in lymphoma-bearing animals compared to disease-free animals. In contrast, in lymphoma-bearing animals with splenomegaly and lymphadenopathy, NKT cells were functionally impaired. In a mouse model of blastoid variant mantle cell lymphoma, treatment of tumor-bearing mice with a potent NKT cell agonist, α-galactosylceramide (α-GalCer), resulted in a significant decrease in disease pathology. Ex vivo studies demonstrated that NKT cells from α-GalCer treated mice produced IFN-γ following α-GalCer restimulation, unlike NKT cells from vehicle-control treated mice. These data demonstrate an important role for NKT cells in the immune response to an aggressive hematologic malignancy like mantle cell lymphoma.

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.

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.

CD5-negative Blastoid Variant Mantle Cell Lymphoma with Complex CCND1/IGH and MYC Aberrations

The coexistence of CCND1/IGH and MYC rearrangements in mantle cell lymphoma (MCL) is a rare finding associated with a very poor prognosis. In this study, a patient with blastoid variant (MCL) is reported. The disease was clinically aggressive and refractory to chemotherapy, and the patient only survived for 1 month following diagnosis. Conventional cytogenetic study, FISH, and multicolor FISH (mFISH) demonstrated the involvement of the BCL1/CCND1 locus in a complex translocation, t(3;11)(q25;p15)t(11;14)(q13;q32). In addition, subclonal abnormalities in the 8q24 region, manifested as a t(8;14)(q24;q32)/MYC rearrangement, were identified. To the best of our knowledge, this is the first MCL case in Korea bearing these complex genomic aberrations.

Novel CRM-1 Inhibitors for Therapy In Mantle Cell Lymphoma

Abstract 2734Chromosomal Region Maintenance 1 (CRM1) overexpression has been associated with cancer progression and mortality in several human cancers, suggesting that activation of nuclear export may play a role in human neoplasia and may serve as a novel target for the treatment of cancers. This overexpression of CRM1 may be related to the export of most tumor suppressor and growth regulatory proteins out of the nucleus, thereby functionally inactivating them. Mantle cell lymphoma (MCL) is an aggressive histotype of B-cell non-Hodgkin lymphoma that is not yet curable. The objective of our study was to investigate the status of CRM1 in MCL, both in MCL cell lines and primary MCL cells, in comparison to normal B cells, and to evaluate the therapeutic efficiency of CRM1 inhibition in MCL in vitro and in vivo, and to elucidate the mechanism of CRM1 inhibitor-mediated MCL cell apoptosis. We used 8 established MCL cell lines and primary cells from 4 patients with relapsed/refractory MCL. KPT185 and KPT276 are novel, highly selective, drug-like small molecular CRM1 inhibitors. Western Blot analysis showed that CRM1 was expressed in both the cytoplasm and nuclei of 8 MCL cell lines. CRM1 was mainly detected in nuclei of normal resting B cells; In contrast, CRM1 was primarily detected in the cytoplasm of freshly isolated primary MCL cells from patients with relapsed/refractory MCL. In 3H-thymidine incorporation assays, inhibition of CRM1 by KPT185 resulted in a significant dose-dependent growth inhibition of 8 MCL cells, with IC50 values range between 10 nM to 120 nM. The blastoid-variant MCL cell lines (Z-138 and Rec-1) were significantly more sensitive to KPT185 than the non-blastoid variant MCL cell lines. Flow cytometry analysis with fluorescence-labeled Annexin V and propidium iodide showed that KPT185 induced MCL cells apoptosis in both time- and dose-dependent manners, but had no effect on cell cycle arrest. MCL cells treated with KPT185 for 12 hours showed caspase 3 activation and PARP cleavage. As shown in Western blot and confocal microscopy, blocking CRM1 activity by KPT185 in MCL cells up-regulated the protein expression of p53, a known CRM1-mediated export protein, and also induced CRM1 translocation to the nucleus and decreased CRM1 expression. In severe combined immunodeficient (SCID) mice bearing palpable Z-138 tumors, treatment with KPT-276 (similar structure to KPT-185 but improved animal pharmacokinetics), 50mg/kg or 150 mg/kg PO QDx5 each week, or cyclophosphamide 100 mg/kg on days 1–3, was initiated. Tumor growth was significantly inhibited (>75%) in all of treatment groups compared with vehicle control. Neutropenia and other cytotoxic-agent specific effects have not been observed in treated animals. In conclusion, CRM1 inhibitors inhibited growth of MCL cells in vitro and in vivo, and induced apoptosis of MCL cells via inhibition of CRM1 expression and blockage of its translocation with functional nuclear proteins. Our data suggest that novel CRM1 inhibitors provide a potential therapy for patients with relapsed/refractory MCL. Disclosures:No relevant conflicts of interest to declare.

Mantle cell leukemia as a cause of leukostasis

Mantle cell leukemia as a cause of leukostasis Daniel Smith1, Christian Cable2, Cary Chisholm1, Walter Linz1, William Koss1, Sheila Dobin1, Edward Rappaport11Department of Pathology, 2Internal Medicine, Scott and White Healthcare/Texas A &amp; M Health Science Center College of Medicine, Temple, TX, USAAbstract: A 72-year-old man was admitted with hypoxemic respiratory distress. Given a white blood cell count of 600 &times; 109/L and symptoms of leukostasis, emergency leukapheresis was initiated. The white blood cell count immediately after the first leukapheresis was paradoxically increased to over 700 &times; 109/L. Peripheral blood smear findings showed morphologically immature mononuclear cells and numerous circulating mitotic figures. Initial flow cytometry results showed a lambda light chain-restricted B lymphoid population positive for CD20, CD19, CD5, and FMC-7, and negative for TdT, CD10, CD23, CD34, CD117, and myeloid markers, suggesting classification as a blastoid variant of mantle cell lymphoma in a leukemic phase. Subsequent testing using DNA fluorescence in situ hybridization was positive for t(11;14), confirming the diagnosis of mantle cell leukemia. Although mantle cell lymphoma occasionally transforms or can even present as leukemia (leukocytes &gt;40 &times; 109/L), it is rare for it to present with such profound leukocytosis and an overwhelming number of pleomorphic/blastoid forms. Although morphology suggested acute lymphoblastic leukemia, a more specific diagnosis of blastoid variant mantle cell lymphoma was obtained in 12 hours by applying complementary techniques of flow cytometry and rapid cytogenetics.Keywords: mantle cell lymphoma, chemotherapy, leukapheresis, lymphocytic leukemia

FDG-PET as a Marker of tumor proliferation Compared to Gene-Expression Proliferation Scores, MIB1%, and LDH In Untreated Mantle Cell Lymphoma (MCL)

AbstractAbstract 3093 Background:Mantle cell lymphoma (MCL) is a biologically heterogeneous disease with marked variation in clinical behavior. Many patients are offered high intensity therapy even though a significant minority can be safely monitored for long periods of time. The ability to precisely define this subset at time of diagnosis would greatly enhance clinical decision-making. Tumor proliferation as measured by gene expression profiling (GEP) has proven to be prognostic in MCL and can segregate patients into quartiles with different survival expectations, but is technically challenging, expensive, and not readily available. MIB1, an antibody against the Ki-67 antigen, detects the number of cells actively dividing in a tissue specimen and also has a well-established correlation with outcomes in MCL, but can have significant inter-observer variability.FDG PET/CT scans are a readily available tool routinely utilized to stage MCL in a qualitative way. Standard uptake values (SUV) on PET scan are assumed to correlate with tumor proliferation, but previous attempts to correlate SUV with markers of proliferation did not include GEP and were not exclusive to patients with MCL. LDH also is a marker of aggressive biology in numerous tumor types and a biologic parameter of the MIPI. Here, we investigated the relationship between SUV values seen on PET scan at baseline in untreated MCL patients as compared to the tumor's proliferation score (PS) as measured by gene expression, MIB1% and serum LDH levels. Methods:The analysis involved untreated MCL patients who had a baseline FDG-PET/CT followed by a pre-treatment biopsy of a lymph node with the highest SUV unless it was considered inaccessible. Analysis of the PET/CT scans was done by an expert in nuclear medicine who was blinded to the outcome of the patients and pathology findings. SUV of biopsied node (SUVnode) and maximum SUV uptake of the entire scan (SUVmax) normalized to body weight were recorded. GEP was done on pre-treatment lymph nodes, and the expression levels of 18 proliferation signature genes were averaged to generate a PS as previously described (Rosenwald, 2003). MIB1% was calculated using image analysis software and was recorded as the number of positive cells/total number of cells in the entire specimen. Result:39 patients were treated between September 2005 and June 2010. Median age was 58 years (41-73) and 77% of patients were male. Simplified MIPI risk groups included 20 low, 14 intermediate and 5 high. 5 patients (13%) were diagnosed with blastoid variants. Pretreatment PET/CT scans were available in 37 patients, nodal biopsies in 28, and PS in 19.Median SUVnode was 5.18 (1.81-12.89, n=27) and median SUVmax for the entire group was 6.40 (2.22-17.5, n=37). SUVnode and SUVmax had virtually identical correlations to PS: r=0.59 (p = 0.007) and r=0.61 (p = 0.006), respectively. Tumors classified as high or low proliferation by PS had a median SUVmax of 11.89 and 5.67, respectively (p = 0.004). In blastoid-variant MCL, the median SUVmax was 12.38 (n=5) while in non-blastoid it was 5.68 (n=32), and 3/5 (60%) tumors with SUVmax > 12 were blastoid variant. MIB1% in lymph node biopsies correlated with both SUVmax, r=0.49 (p = 0.015) and PS, r=0.83 (p < 0.001). LDH correlated highly with PS, r=0.74 (p < 0.001) but less so with SUV, r=0.37 (p = 0.02). Table 1 shows the distribution of these parameters within Quartiles based on PS.Table 1Correlation of PS and other markers of tumor proliferation (median value given)PSSUVmaxMIB1%LDHQuartile 15.5811126Quartile 26.1611159Quartile 310.7320192Quartile 412.6455278 Conclusion:SUVmax on baseline FDG-PET scans correlated well with markers of tumor proliferation such as PS and MIB1% in untreated MCL. However, in our data, both MIB1% and LDH correlated better with PS thanSUVmax. Thus, SUVmax as measured by FDG-PET appears less specific for tumor proliferation and may be influenced by other aspects of tumor biology. The possible biologic differences in tumors with high and low SUV are the focus of ongoing investigations. While high SUV values typically identify tumors with high proliferation and/or blastoid morphology, low and intermediate SUV values do not reliably correlate with tumor proliferation. This might be improved with alternative PET radiotracers such as fluorothymidine (FLT) that more specifically measures proliferation. Disclosures:No relevant conflicts of interest to declare.