Overcoming Drug Resistance in Mantle Cell Lymphoma Using a Combination of Dose-Dense and Intense Therapy

2010 ◽  
Vol 28 (6) ◽  
pp. 654-660 ◽  
Author(s):  
Christopher A. Crout ◽  
Liang-Piu Koh ◽  
Jon P. Gockerman ◽  
Joseph O. Moore ◽  
Carlos DeCastro ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Mantle Cell ◽  
Dose Dense

scholarly journals Bifurcated BACH2 control coordinates mantle cell lymphoma survival and dispersal during hypoxia

Blood ◽  
2017 ◽  
Vol 130 (6) ◽  
pp. 763-776 ◽  
Author(s):  
Han Zhang ◽  
Zheng Chen ◽  
Roberto N. Miranda ◽  
L. Jeffrey Medeiros ◽  
Nami McCarty
Keyword(s):  
Drug Resistance ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Physiological Conditions ◽  
Key Points ◽  
Mantle Cell

Key Points Downregulation of BACH2 increases MCL proliferation, dispersal, and drug resistance. Distinct crosstalk between BACH2 and HIF-1α under different physiological conditions modifies MCL properties.

Multimodal Dose Dense Therapy for Mantle Cell Lymphoma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1163-1163
Author(s):  
Sam O. Wanko ◽  
Jon P. Gocherman ◽  
Joseph O. Moore ◽  
Carlos Decastro ◽  
Robert Prosnitz ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Induction Therapy ◽  
Response Rate ◽  
Cell Lymphoma ◽  
High Dose ◽  
Event Free Survival ◽  
Free Survival ◽  
Mantle Cell ◽  
Dose Dense

Abstract BACKGROUND: Mantle cell lymphoma (MCL) typically has a poor outcome with overall survival of only 3–4 years. Higher treatment response and event-free survival has been demonstrated with aggressive high dose chemotherapy followed by autologous hematopoietic stem cell support, though long term cure rates remain unclear(Dreger P. Hematol J. 2000;vol.2). Modest response rates have also been reported with the monoclonal antibody (MoAb) rituximab and ALEMTUZUMAB (Foran, JM. JCO 2000; vol. 2. Faderl S. Blood 2003; vol. 9). We therefore combined dose-dense therapy with MoAbs to explore response rate and event free survival (EFS) in mantle cell lymphoma. The strength of this trial design is ability to follow all patients from induction chemotherapy through high dose therapy and transplant in order to gauge clinical outcome on all enrolled patients, not just the subpopulation who is able to proceed to high dose therapy. PATIENTS AND METHODS: Induction therapy consisted of 1 cycle of high dose cytarabine (3gm/m2 IV over 1 hour Q12H for 8 doses), mitoxantrone (10mg/m2 daily for 3 days), and ALEMTUZUMAB 30mg IV 3 times a week for 6 weeks with growth factor support. All responding patients were mobilized with cyclophosphamide 4gm/m2 and G-CSF 10 mcg/kg/day and/or bone marrow harvest. The transplant preparative regimen was carmustine 15mg/kg over 2 hours day -6, etoposide 60mg/kg over 4 hours day -4, and cyclophosphamide 100mg/kg over 2 hours day -2 followed by autologous reinfusion on day zero. Consolidation was given with rituximab 375mg/m2 weekly for 4 doses at 6 weeks and 6 months post transplant. RESULT: 9 patients with advanced disease (7 stage IV, 1 stage III, 1 stage IIA) and median age of 60 (48 – 65 years) have been accrued and treated since February 2003. Four were newly diagnosed and 5 had relapsed/refractory disease. Seventy eight percent (7/9) had complete response and 22% (2/9) had partial response (PR) following induction therapy. One patient had severe infection after induction and was unable to proceed to transplant. Another had constitutional decline preventing further therapy and each died within 4 months of withdrawal from the protocol. Both had relapse/refractory disease at accrual. The remaining 7 patients proceeded to the transplant phase. With a median follow-up of 7 months (range 3–16 months), all 7 patients remain in CR for 1 –16 months. Significant induction therapy toxicity included neutropenia in all 9 patients with average duration of 10.7 days, non-disseminated CMV reactivation in 44% of patients, one overwhelming fungal infection, and one patient with delay in engraftment. Figure Figure CONCLUSION: Our preliminary data show a high induction and transplant phase completion rate, manageable toxicity, and excellent overall response rate in this group of elderly patients with advanced disease. Larger numbers of patients and longer follow-up is needed to confirm these promising results.

High Complete Response Rates with Dose Dense/Dose Intense Chemotherapy Plus Radioimmunotherapy in High Risk Diffuse Large B Cell and Mantle Cell Lymphoma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2681-2681 ◽  
Author(s):  
Anne W Beaven ◽  
David A. Rizzieri ◽  
Zachary Powell ◽  
Zhiguo Li ◽  
Peggy Alton ◽  
...  
Keyword(s):  
High Risk ◽  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Complete Response ◽  
Mantle Cell ◽  
Dose Dense ◽  
Large B Cell

Abstract Abstract 2681 Background: Despite recent advances, the 5 year overall survival for patients with high risk diffuse large B cell lymphoma (DLBCL) is approximately 50% and there is still no known cure for patients with mantle cell lymphoma (MCL). This phase II study of multimodal dose dense therapy evaluated 2 courses of dose intense chemotherapy followed by radioimmunotherapy (RIT) consolidation in patients with previously untreated, mantle cell or high/high intermediate (int) risk aggressive B cell lymphoma. Aim: To evaluate the efficacy and safety of dose intense/dose dense, multimodal chemo-immunotherapy combined with RIT. Methods: Patients with untreated MCL or high int/high risk DLBCL were enrolled. Treatment regimen involved 3 phases of therapy: induction 1, induction 2 and consolidation with RIT (Table 1). Induction 2 occurred approximately 5 weeks after induction 1 and RIT was given 12–24 weeks after rituximab was completed. Patients were evaluated after each treatment phase and those with stable disease (SD) or better and blood count recovery could proceed to the next phase of therapy. Results: Thirty nine patients (pts) with high/high int risk DLBCL (n=25) or MCL (n=14) were enrolled. The median age was 60 years (range 21–80). Toxicity: Common, anticipated toxicities in the induction phases were thrombocytopenia, neutropenia, nausea, fatigue, and anemia. During Ind1 (n=39), grade (gr) III mucositis occurred in 13 pts (33%) and febrile neutropenia (FN) in 31 (79%). Three pts did not proceed to Ind2 due to death (1 candidemia, 1 septic knee prosthesis, 1 from complications of colectomy for prolonged diverticulitis after count recovery) and 2 withdrew to pursue less intense chemotherapy. During Ind2 (n=34) gr III mucositis occurred in 12pts (35%) and FN in 24 (67%). Two pts had gr III/IV cerebellar toxicity that was disabling in 1 pt. Of the 34 pts who received the Ind2, 9 did not receive RIT due to progressive disease (PD) (4), prolonged cytopenias (4), or diagnosis of pancreatic cancer (1). Twenty five pts received RIT and 3 (12%) had FN, 20 (80%) had gr III/IV neutropenia, 23 (92%) had gr III/IV thrombocytopenia, 1 pt died from bacteremia. Two pts developed myelodysplasia 21 and 48 months after starting therapy. Response: Pts were evaluated for response after Ind1, Ind2 and RIT. 38/39 pts were evaluable for response, with 1 pt withdrawing prior to assessment. The pts who died prior to response evaluation were counted as non-responders. The best overall response rate (ORR) was 95% (36/38) with a complete response rate (CR) of 84% (32/38). See tables 2 and 3 for more detailed response data by phase of treatment and disease type. After a median follow up of 17.2 months, 30 pts (77%) are alive (see figure). The median overall survival for MCL has not been reached and is 36.5 months for DLBCL. Deaths were from Hodgkin lymphoma (1), infection (3), DLBCL (2), complications of surgery (1), MCL (2). The median progression free survival is 36.5 months with 11/14 (79%) MCL and 14/25 (56%) DLBCL pts alive and in continued CR. Conclusion: The combination of dose dense, dose intense chemotherapy, monoclonal antibody, and RIT demonstrates considerable efficacy, despite expected toxicity, in high risk DLBCL and MCL pts. The response rates seen in this study are higher than expected from standard R-CHOP in this pt population. Further follow up to determine impact on OS and long term complications will be required to confirm these promising outcomes. Disclosures: Beaven: Glaxo Smith Kline: Family Member Employed by GSK. Off Label Use: Tositumomab is approved for use in relapsed/refractory low grade CD20 positive NHL. It is not FDA approved for first line use in diffuse large B cell lymphoma or mantle cell lymphoma. Neither cytarabine nor etoposide are approved for use in non-Hodgkin lymphoma. Rizzieri:Glaxo Smith Kline: Speakers Bureau. Moore:Glaxo Smith Kline: Speakers Bureau.

scholarly journals MCL-101: Using the Iron Chelator Deferasirox to Overcome Drug Resistance in Mantle Cell Lymphoma

2021 ◽  
Vol 21 ◽  
pp. S408-S409
Author(s):  
Aladin Samara ◽  
Saar Shapira ◽  
Ido Lubin ◽  
Pia Raanani ◽  
Galit Granot
Keyword(s):  
Drug Resistance ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Iron Chelator ◽  
Mantle Cell

scholarly journals BMP7 Expression Correlates with Secondary Drug Resistance in Mantle Cell Lymphoma

PLoS ONE ◽  
2013 ◽  
Vol 8 (9) ◽  
pp. e73993 ◽  
Author(s):  
Valérie Camara-Clayette ◽  
Serge Koscielny ◽  
Sébastien Roux ◽  
Thierry Lamy ◽  
Jacques Bosq ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Mantle Cell

Migratory Activity and Stromal Cell Adhesion of Mantle Cell Lymphoma Cells Can Be Diminished by Blocking of VLA-4 and CXCR4 Receptors

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2825-2825 ◽  
Author(s):  
Antonina Kurtova ◽  
Archie Tamayo ◽  
Richard J. Ford ◽  
Jan A. Burger
Keyword(s):  
Drug Resistance ◽  
Cell Adhesion ◽  
Mantle Cell Lymphoma ◽  
Adhesion Molecules ◽  
Stromal Cells ◽  
Chemokine Receptors ◽  
Stromal Cell ◽  
Cell Lymphoma ◽  
Mantle Cell ◽  
And Function

Abstract Mantle cell lymphoma (MCL) is an aggressive lymphoma that generally is associated with a rapid dissemination of the malignant B-cells and a high risk of relapse. Chemokine receptors and adhesion molecules play key roles in normal B cell migration and homing to distinct microenvironments, but their expression and function in MCL is largely unknown. In this study, we profiled the expression and function of chemokine receptors and adhesion molecules (CXCR4, CXCR5, CXCR3, CD49d/VLA-4, CD44, and CD62L) in MCL cell lines (SP-53, MINO, JeKo-1 and Granta-519) and primary MCL cells. Except for the EBV-positive cell line Granta 519, all MCL lines displayed high levels of CXCR4, CXCR5, CD49d and CD44. Primary MCL cells from different patients (n=6) displayed a similar immunophenotype. We then analyzed chemotaxis of MCL cells towards CXCL12 (200 ng/ml) and CXCL13 (1μg/ml) in transwell assays. 35.7±5.7% of input SP-53, 25.8±2.8% of MINO, and 6.7±0.9% of JeKo-1 cells migrated towards CXCL12 within 3 hours (mean±SEM, triplicates). 43.4±9.8% of input SP-53, 16.7±2.8% of MINO, and 4.3±0.5% of JeKo-1 cells migrated toward CXCL13. Granta-519 did not demonstrate any significant chemotaxis. Pre-treating the cells with a CXCR4 antagonist (AMD3100, Plerixafor) effectively blocked chemotaxis towards CXCL12. Marrow stromal cells (MSC) constitutively secrete CXCL12 and provide ligands for VLA-4 integrins. These two molecules now can be targeted clinically using CXCR4 antagonists or monoclonal antibodies (mAbs), respectively. In co-cultures with MSC, SP-53 and MINO displayed abundant spontaneous migration beneath MSC (pseudoemperipolesis/PEP). Therefore we examined whether blocking of CXCR4 or VLA-4 affects the PEP of MCL cells. Pre-incubation of SP-53 or MINO cells with AMD3100 reduced PEP to levels that were 49.4±1.5% (p<.07) or 11.7±1.7% (p<.04) of controls. Pretreatment with anti-VLA-4 antibodies (Natalizumab) also resulted in significant decrease of PEP to levels that were 5.8±1.4% (p<.02) in SP-53 and 2.2±0.6% (p<.01) in MINO cells. Pre-incubation with a cyclic peptide inhibitor with the minimal VLA-4 binding motif “LDV” also significantly reduced PEP of MCL cells to 22.1±4.0% (p<.006) in SP-53 and 7.1±1.9% (p<.005) in MINO cells. MCL cells treated with 10 μM fludarabine (F-ara-A) in suspension cultures resulted in high levels of apoptosis in MCL cells within 24 to 72 hrs. We found that co-culture with MSC significantly reduced F-ara-A-induced apoptosis, a primary drug resistance mechanism termed cell adhesion-mediated drug resistance (CAM-DR). Interestingly, the MCL cell fraction that had migrated into the stromal cell layer was particularly protected from the cytotoxic effect of F-ara-A. As such, clinical targeting of CXCR4 and VLA-4 integrins in MCL may not only antagonize the migration and homing associated with the dissemination of the disease, but also disrupt the adhesion to stromal cells, help to overcome CAM-DR, and thus make MCL cells more accessible to conventional drugs. Collectively, our studies provide a rationale to further explore the efficacy of combinations of CXCR4- and/or VLA-4 antagonists with conventional drugs in patients with this disease. This approach may lead to new therapeutic avenues for MCL patients.

Sign in / Sign up

Export Citation Format

Share Document