T(11;14)(q13;q32) in Mantle Cell Lymphoma Patients Is Present Only on Mature Malignant Cells. Fluorescence-Activated Cell Sorting and Fluorescence in Situ Hybridization Analysis

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4405-4405
Author(s):  
Vladimir I. Vorobyev ◽  
Evgenii’ M Gretsov ◽  
Tatyana N Obukhova ◽  
Elena V Domracheva ◽  
Yuri Yu Lorie ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
Mantle Cell Lymphoma ◽  
Cell Sorting ◽  
Cell Lymphoma ◽  
Acid Mixture ◽  
High Dose ◽  
Fish Analysis ◽  
Fluorescence Activated Cell Sorting ◽  
Mantle Cell

Abstract Abstract 4405 Background: Mantle cell lymphoma (MCL) is a distinct incurable B-cell neoplasm with a median survival of 3 to 5 years. t(11;14)(q13;q32) is the hallmark of the disease leading to overexpression of protooncogene cyclin D1. At least 60% of MCL patients have unmutated VH genes. Chemoresistance to conventional treatment and continuous disease relapses even after high dose therapy and autologous stem cell transplantation define the clinical course of the disease. A possible cause of this frequent failures may be that t(11;14)(q13;q32) occurs in early hematopoietic precursors, capable of multilineage differentiation. Aim: evaluation of t(11;14)(q13;q32) in different hematopoietic lineages of MCL patients. Methods: Bone marrow mononuclears from 12 MCL patients (including pleomorphic and blastoid variants) were sorted by Fluorescence-Activated Cell Sorting (BD FACSVantage SE) to divide the following cell lineages: CD45+CD34+ (progenitor cells); CD45+CD5+CD19+light chain Ig (mantle cell lymphoma); CD45+CD5-CD19+ (normal B-cells); CD45+CD14+ (monocytes); CD45+CD3+ (T-cells); CD45-GlyA+ (erythrokaryocytes) and granulocytes by light scattering, excluding CD14+CD45+ cells. The purity of sorted cells was checked by flow cytometry (BD FACSCanto II) and correlated to the number of sorted cells – if there were more than 50 thousands cells the purity was more than 92% (usually more 97%), but if there were less than 20 thousands cells the purity was 80% (never less). After sorting cells in the test-tube were washed from the PBS, fixed in methanol and glacial acetic acid mixture and layered onto slides by Cytospin centrifuge (Cellspin II Tharmac). The probes have been denatured at 75°C for 2 minutes, and hybridized with dual fusion LSI IGH-CCND1 probes (Vysis Inc.) at 37°C for 17–20 hours. Signals were visualized with Olympus IX-61 microscope with triple filter cube (DAPI / FITC / TexasRed). Results: t(11;14)(q13;q32) was present in 97% of sorted mantle cell lymphoma cells (range 84–100%), whereas in cells of all other lineages including normal B-cells t(11;14)(q13;q32) was not found at all. However, direct assessment of t(11;14)(q13;q32) in CD34+CD45+ cells and in normal B-cells was difficult due to the small number of these cells. In one case (classic variant MCL) we have sorted two “independent” cell populations 1 log different in the level of expression CD5: CD5dimCD19+ and CD5+CD19+. In both subpopulations t(11;14)(q13;32) was detected in 98,5% cell nuclei, indicating no correlation between CD5 level and fusion gene expression. In three cases using together FACS and FISH we were able to detect the population of MCL cells in bone marrow as small as 0,1–0,05%, whereas histology examination and standard FISH analysis failed to detect bone marrow involvement. Conclusion: Out data give evidence for the absence of t(11;14)(q13;q32) in early hematopoetic cells. FACS allows increase FISH sensitivity in 100–1000 times. Disclosures: No relevant conflicts of interest to declare.

Sequential radioimmunotherapy with tositumomab/Iodine I131 tositumomab followed by CHOP for mantle cell lymphoma demonstrates RIT can induce molecular remissions

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7560-7560 ◽  
Author(s):  
A. D. Zelenetz ◽  
A. Noy ◽  
N. Pandit-Taskar ◽  
M. Scordo ◽  
I. Rijo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mantle Cell Lymphoma ◽  
Residual Disease ◽  
Cell Lymphoma ◽  
Alternative Therapy ◽  
Active Agent ◽  
Initial Therapy ◽  
High Dose ◽  
Chop Chemotherapy ◽  
Mantle Cell

7560 Background: Mantle cell lymphoma remains a clinical challenge particularly for pts not candidates for consolidation with ASCT or treatment with leukemia induction regimens. Methods: We investigated sequential radioimmunotherapy (RIT) cytoreduction with tositumomab/Iodine I131 tositumomab followed by CHOP chemotherapy as initial therapy for patients either ineligible for or unwilling to undergo high dose therapy and stem cell transplantation. In addition, pts had to have less than 25% of the intratrabecular bone marrow space involved with lymphoma. Results: Twenty-five patients (pts) were enrolled but only 24 were treated with the therapeutic dose of RIT because a manufacturing problem prevented the treatment of one patient. The median age was 66 (45–80), there were 23 men and 2 women. All patients had advanced stage (III/IV) disease and bone marrow was involved in 48% and the GI tract was involved in 48% of the patients. The overall response rate (ORR) to RIT was 83% (CR/CRu 46%; PR 38%). Two pts withdrew consent following the RIT (and are censored from that point); 1 pt with disease progression requiring alternative therapy is included in EFS and OS analyses. Twenty-one pts proceeded to the CHOP consolidation and 19 completed planned therapy (1 pt died of a CVA; 1 pt chose not to complete chemotherapy after two cycles of CHOP). At the completion of delivered therapy the ORR was 86% (CR/CRu 67%, PR 19%). The median follow up is 2.1 years (0.7 to 4.2). The median EFS was 1.4 years though there have been no events beyond 1.7 years with 7 pts at risk; median OS has not been reached (92% at 2.1 years). Minimal residual disease (MRD) was evaluated with a clonotypic PCR (cPCR) capable of detecting about 1:105 tumor cells; this assay was informative in 17 pts. Following induction with RIT 6 pts (46%) were molecularly negative in blood and bone marrow. Despite the increase in clinical CR following CHOP consolidation, no additional pts became molecularly negative. Conclusions: RIT with tositumomab/iodine I131 tositumomab is a very active agent in the treatment of MCL; unfortunately, MRD is not effectively eliminated by subsequent CHOP chemotherapy. We are planning to explore chemotherapy induction followed by RIT. [Table: see text]

scholarly journals Mantle Zone Cell Lymphomas. New Opportunities for Diagnosis and Treatment (Epidemiological Research)

2020 ◽  
Vol 9 (4) ◽  
pp. 261-265
Author(s):  
E. I. Kankumasheva ◽  
Ch. Kh. Valiakhmetova
Keyword(s):  
Bone Marrow ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Molecular Genetic ◽  
Epidemiological Data ◽  
Patient Specific ◽  
High Dose ◽  
Rare Type ◽  
Genetic Characteristics ◽  
Mantle Cell

Introduction. Mantle cell lymphoma is a rare type of B-cell non-Hodgkin lymphoma. According to statistics the incidence of this disorder amounts to 2-3 per 100,000 people; this is about 6% of all non-Hodgkin lymphomas. It has been established that various molecular genetic characteristics of mantle cell lymphoma patients may present opportunities for a patient-specific approach to the disease prognosis and treatment strategy.Materials and methods. The paper presents a retrospective analysis of 45 mantle cell lymphoma patients treated at the GAUZ RKOD of the Ministry of Healthcare from 2015 until now. The data used in the analysis included clinical examination, lab panels, PET CT, tumour and bone marrow biopsy specimen cytology, histology and immunohistochemistry. We analysed the epidemiological data, the patients’ clinical presentation characteristics, treatment approaches, immediate and long-term outcomes.Results and discussion. We have established that the pathological process most frequently involves bone marrow (44%) and spleen (41%). The MIPI scores distribution was as follows: high in 14 (30%), medium in 20 (45%), low in 11 (41%). Ki67 was recorded at under 30% in four cases, in others it amounted to over 30%. In 2015–2017 patients were treated with the R-CHOP protocol with the following support with rituximab. PFS averaged at 20 months, 8 (17%) of patients remain in lasting remission (since 2015). In 2017 the R-BAC (high dose cytarabine for SCT candidates) and R-B (for the elderly and comorbid patients) became protocols of first line. Since 2018 eight patients have undergone auto-SCT (at the first late recurrence) as a treatment consolidation stage. As of now 13 patients have been examined in federal centres for del17p and the TP53 mutation.Conclusion. We have demonstrated the need for and the option of treatment depending on the results of molecular genetic testing of mantle cell lymphomas.

Update of a GITIL Cohort Study: Frontline High Dose Sequential Chemotherapy with Rituximab and Autologous Stem Cell Transplantation Induces a High Rate of Long-Term Remissions in Patients with Mantle Cell Lymphoma

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1282-1282 ◽  
Author(s):  
Sergio Cortelazzo ◽  
Michele Magni ◽  
Corrado Tarella ◽  
Michael Mian ◽  
Atto Billio ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cohort Study ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
High Dose ◽  
Sequential Chemotherapy ◽  
Mantle Cell ◽  
Group 2 ◽  
Group 1

Abstract We updated a cohort study with the aim of evaluating if an up-front Rituximab supplemented high-dose sequential chemotherapy (R-HDS), supported by autologous bone marrow transplantation (ASCT) can induce log-term remissions in Mantle Cell Lymphoma (MCL), with an acceptable toxic profile. From 1997 to 2005, 77 consecutive MCL patients, <61 year old, considered suitable for ASCT in 11 Italian cancer centres were enrolled in this study (Group 1). Their clinical outcome was compared with that of 79 age-matched historic controls treated between 1978 and 1999 with standard-dose anthracyclin or fludarabine containing regimens (group 2). The majority of both groups had an advanced stage, bone marrow infiltration and >1 IPI risk factors, while >1 extranodal sites prevailed in Group 1 and a poor ECOG-PS in Group 2. After 2–3 cycles of either doxorubicin- or cisplatin-containing chemotherapy, Group 1 received R-HDS including: HD-cyclophosphamide (CTX) 7 gr/sqm and HD-Ara-C (2 g/sqm every 12 hours for 6 days), followed by HDS HD-melphalan (180 mg/sqm) and/or HD-mitoxantrone plus melphalan (60 and 180 mg/sqm) and ASCT. Rituximab (375 mg /sqm) was given for a total of 6 doses, twice after HD-CTX and HD-Ara-C, as in vivo purging before CD34+ cells harvest and twice after ASCT. Sixty-nine patients (90%) in Group 1 completed the planned program and a median number of 6.3 x 10^6 cells CD34+/kg were transplanted. In Group 2, 85% of patients received the planned chemotherapy. The CR rate was 86% in Group 1 and 35% in Group 2 and the treatment-related mortality was 1.3% and 0.8%, respectively. Moreover, in Group 1, 4 patient developed sMDS, and 4 died of solid tumors (n=3), or septic shock (n=1). After a median follow-up of 50 months (range 3–111) in Group 1 and 37 months (range 1–141) in Group 2, the rate of 1st CCR was 65% and 14%, respectively. The 5-year projected OS, EFS and DFS were 74%, 61% and 70%, in Group 1 and 31%, 14% and 25%, in Group 2, respectively. Cox multivariate analysis failed to identify within potential prognostic markers factors predictive for OS and EFS. In conclusion, R-HDS induces long-term remissions with a manageable toxicity in patients with newly diagnosed MCL. Studies comparing this program with other intensive regimens are needed for ascertaining the role of R-HDS in the treatment of this otherwise incurable disease.

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

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Veronica Ortega ◽  
Christina Mendiola ◽  
Juana Rodriguez ◽  
William Ehman ◽  
You-Wen Qian ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mantle Cell Lymphoma ◽  
Copy Number ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Chromosome Analysis ◽  
Copy Number Gain ◽  
Fish Analysis ◽  
Mantle Cell ◽  
Microarray Studies

Abstract Background Mantle 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 presentation Here 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. Conclusion To 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.

scholarly journals Impact of Mantle Cell Lymphoma Contamination of Autologous Stem Cell Grafts on Outcome After High-Dose Chemotherapy

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2558
Author(s):  
Malte Roerden ◽  
Stefan Wirths ◽  
Martin Sökler ◽  
Wolfgang A. Bethge ◽  
Wichard Vogel ◽  
...  
Keyword(s):  
Stem Cell ◽  
Mantle Cell Lymphoma ◽  
Clinical Decision Making ◽  
Cell Lymphoma ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Increased Risk ◽  
Mantle Cell ◽  
Autologous Grafts

Novel predictive factors are needed to identify mantle cell lymphoma (MCL) patients at increased risk for relapse after high-dose chemotherapy and autologous hematopoietic stem cell transplantation (HDCT/Auto-HSCT). Although bone marrow and peripheral blood involvement is commonly observed in MCL and lymphoma cell contamination of autologous stem cell grafts might facilitate relapse after Auto-HSCT, prevalence and prognostic significance of residual MCL cells in autologous grafts are unknown. We therefore performed a multiparameter flow cytometry (MFC)-based measurable residual disease (MRD) assessment in autologous stem cell grafts and analyzed its association with clinical outcome in an unselected retrospective cohort of 36 MCL patients. MRD was detectable in four (11%) autologous grafts, with MRD levels ranging from 0.002% to 0.2%. Positive graft-MRD was associated with a significantly shorter progression-free and overall survival when compared to graft-MRD negative patients (median 9 vs. 56 months and 25 vs. 132 months, respectively) and predicted early relapse after Auto-HSCT (median time to relapse 9 vs. 44 months). As a predictor of outcome after HDCT/Auto-HSCT, MFC-based assessment of graft-MRD might improve risk stratification and support clinical decision making for risk-oriented treatment strategies in MCL.

Prominent intrasinusoidal infiltration of the bone marrow by mantle cell lymphoma

2003 ◽  
Vol 34 (8) ◽  
pp. 789-791 ◽  
Author(s):  
Andre A Schenka ◽  
Randy D Gascoyne ◽  
Eliane Duchayne ◽  
Georges Delsol ◽  
Pierre Brousset
Keyword(s):  
Bone Marrow ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Mantle Cell

scholarly journals The B-cell tumor–associated antigen ROR1 can be targeted with T cells modified to express a ROR1-specific chimeric antigen receptor

Blood ◽  
2010 ◽  
Vol 116 (22) ◽  
pp. 4532-4541 ◽  
Author(s):  
Michael Hudecek ◽  
Thomas M. Schmitt ◽  
Sivasubramanian Baskar ◽  
Maria Teresa Lupo-Stanghellini ◽  
Tetsuya Nishida ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Chimeric Antigen Receptor ◽  
Cell Lymphoma ◽  
Embryonic Stem ◽  
Antigen Receptor ◽  
Orphan Receptor ◽  
Mantle Cell

Monoclonal antibodies and T cells modified to express chimeric antigen receptors specific for B-cell lineage surface molecules such as CD20 exert antitumor activity in B-cell malignancies, but deplete normal B cells. The receptor tyrosine kinase-like orphan receptor 1 (ROR1) was identified as a highly expressed gene in B-cell chronic lymphocytic leukemia (B-CLL), but not normal B cells, suggesting it may serve as a tumor-specific target for therapy. We analyzed ROR1-expression in normal nonhematopoietic and hematopoietic cells including B-cell precursors, and in hematopoietic malignancies. ROR1 has characteristics of an oncofetal gene and is expressed in undifferentiated embryonic stem cells, B-CLL and mantle cell lymphoma, but not in major adult tissues apart from low levels in adipose tissue and at an early stage of B-cell development. We constructed a ROR1-specific chimeric antigen receptor that when expressed in T cells from healthy donors or CLL patients conferred specific recognition of primary B-CLL and mantle cell lymphoma, including rare drug effluxing chemotherapy resistant tumor cells that have been implicated in maintaining the malignancy, but not mature normal B cells. T-cell therapies targeting ROR1 may be effective in B-CLL and other ROR1-positive tumors. However, the expression of ROR1 on some normal tissues suggests the potential for toxi-city to subsets of normal cells.

scholarly journals High-dose cytarabine does not overcome the adverse prognostic value of CDKN2A and TP53 deletions in mantle cell lymphoma

Blood ◽  
2015 ◽  
Vol 126 (5) ◽  
pp. 604-611 ◽  
Author(s):  
Marie-Hélène Delfau-Larue ◽  
Wolfram Klapper ◽  
Françoise Berger ◽  
Fabrice Jardin ◽  
Josette Briere ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Prognostic Value ◽  
Cell Lymphoma ◽  
Standard Of Care ◽  
High Dose ◽  
Current Standard ◽  
Ki 67 ◽  
Key Points ◽  
Mantle Cell ◽  
High Dose Cytarabine

Key Points CDKN2A and TP53 deletions remain of bad prognostic value in younger MCL patients treated according to the current standard of care. CDKN2A and TP53 deletions have independent deleterious effects and should be considered for treatment decisions in addition to MIPI and Ki-67 index.

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